Cancers

Editorial

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4 pages, 190 KiB

Open AccessEditorial

Targeted Therapies for Melanoma

by Karel Smetana, Jr., Lukáš Lacina and Ondřej Kodet

Cancers 2020, 12(9), 2494; https://doi.org/10.3390/cancers12092494 - 3 Sep 2020

Cited by 8 | Viewed by 2685

Abstract

The incidence of cutaneous malignant melanoma (CMM) is significantly increasing worldwide.[...] Full article

(This article belongs to the Special Issue Targeted Therapies for Melanoma)

Research

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22 pages, 4724 KiB

Open AccessArticle

Inflammasome Sensor NLRP1 Confers Acquired Drug Resistance to Temozolomide in Human Melanoma

by Zili Zhai, Jenny Mae Samson, Takeshi Yamauchi, Prasanna K. Vaddi, Yuko Matsumoto, Charles A. Dinarello, Dinoop Ravindran Menon and Mayumi Fujita

Cancers 2020, 12(9), 2518; https://doi.org/10.3390/cancers12092518 - 4 Sep 2020

Cited by 15 | Viewed by 3204

Abstract

Cancer cells gain drug resistance through a complex mechanism, in which nuclear factor-κB (NF-κB) and interleukin-1β (IL-1β) are critical contributors. Because NACHT, LRR and PYD domains-containing protein (NLRP) inflammasomes mediate IL-1β maturation and NF-κB activation, we investigated the role of inflammasome sensor NLRP1 [...] Read more.

Cancer cells gain drug resistance through a complex mechanism, in which nuclear factor-κB (NF-κB) and interleukin-1β (IL-1β) are critical contributors. Because NACHT, LRR and PYD domains-containing protein (NLRP) inflammasomes mediate IL-1β maturation and NF-κB activation, we investigated the role of inflammasome sensor NLRP1 in acquired drug resistance to temozolomide (TMZ) in melanoma. The sensitivity of melanoma cells to TMZ was negatively correlated with the expression levels of O⁶-methylguanine-DNA methyltransferase (MGMT), the enzyme to repair TMZ-induced DNA lesions. When MGMT-low human melanoma cells (1205Lu and HS294T) were treated with TMZ for over two months, MGMT was upregulated, and cells became resistant. However, the resistance mechanism was independent of MGMT, and the cells that acquired TMZ resistance showed increased NLRP1 expression, NLRP inflammasome activation, IL-1β secretion, and NF-κB activity, which contributed to the acquired resistance to TMZ. Finally, blocking IL-1 receptor (IL-1R) signaling with IL-1R antagonist decreased TMZ-resistant 1205Lu tumor growth in vivo. Although inflammation has been associated with drug resistance in various cancers, our paper is the first to demonstrate the involvement of NLRP in the development of acquired drug resistance. Because drug-tolerant cancer cells become cross-tolerant to other classes of cancer drugs, NLRP1 might be a suitable therapeutic target in drug-resistant melanoma, as well as in other cancers. Full article

(This article belongs to the Special Issue Targeted Therapies for Melanoma)

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17 pages, 3189 KiB

Open AccessArticle

Targeted and Checkpoint Inhibitor Therapy of Metastatic Malignant Melanoma in Germany, 2000–2016

by Peter Hellmund, Jochen Schmitt, Martin Roessler, Friedegund Meier and Olaf Schoffer

Cancers 2020, 12(9), 2354; https://doi.org/10.3390/cancers12092354 - 20 Aug 2020

Cited by 8 | Viewed by 2771

Abstract

Targeted therapies (TT) and immune checkpoint inhibitors (ICI) have become increasingly important in the treatment of metastatic malignant melanoma in recent years. We examined implementation and effectiveness of these new therapies over time in Germany with a focus on regional differences. We analyzed [...] Read more.

Targeted therapies (TT) and immune checkpoint inhibitors (ICI) have become increasingly important in the treatment of metastatic malignant melanoma in recent years. We examined implementation and effectiveness of these new therapies over time in Germany with a focus on regional differences. We analyzed data from 12 clinical cancer registries in 8 federal states in Germany over the period 2000–2016. A total of 3871 patients with malignant melanoma in Union internationale contre le cancer (UICC) stage IV at primary diagnosis (synchronous metastases) or with metachronous metastases were included. We investigated differences in survival of patients treated with new and conventional therapies by log-rank tests for Kaplan–Meier curves. Cox regression models were estimated to adjust therapy effects for demographic, regional, and prognostic factors. New systemic therapies were increasingly applied throughout Germany. TT were most frequently documented in Eastern Germany (East: 11.2%; West: 6.3%), whereas ICI therapies were more frequently used in Western Germany (East: 1.7%; West: 3.9%). TT had a relevant influence on patient survival (hazard ratio (HR) = 0.831; 95%-CI = (0.729; 0.948)). Survival was worse in Eastern Germany (HR = 1.470; 95%-CI = (1.347; 1.604)) relative to Western Germany. Treatment and survival prospects of patients with melanoma differed considerably between Western and Eastern Germany. The differences in regional medication behavior and survival require further exploration. Full article

(This article belongs to the Special Issue Targeted Therapies for Melanoma)

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11 pages, 618 KiB

Open AccessArticle

Pimasertib Versus Dacarbazine in Patients With Unresectable NRAS-Mutated Cutaneous Melanoma: Phase II, Randomized, Controlled Trial with Crossover

by Celeste Lebbé, Caroline Dutriaux, Thierry Lesimple, Willem Kruit, Joseph Kerger, Luc Thomas, Bernard Guillot, Filippo de Braud, Claus Garbe, Jean-Jacques Grob, Carmen Loquai, Virginia Ferraresi, Caroline Robert, Paul Vasey, Robert Conry, Richard Isaacs, Enrique Espinosa, Armin Schueler, Giorgio Massimini and Brigitte Dréno

Cancers 2020, 12(7), 1727; https://doi.org/10.3390/cancers12071727 - 29 Jun 2020

Cited by 34 | Viewed by 3624

Abstract

This study investigated the efficacy and safety of pimasertib (MEK1/MEK2 inhibitor) versus dacarbazine (DTIC) in patients with untreated NRAS-mutated melanoma. Phase II, multicenter, open-label trial. Patients with unresectable, stage IIIc/IVM1 NRAS-mutated cutaneous melanoma were randomized 2:1 to [...] Read more.

This study investigated the efficacy and safety of pimasertib (MEK1/MEK2 inhibitor) versus dacarbazine (DTIC) in patients with untreated NRAS-mutated melanoma. Phase II, multicenter, open-label trial. Patients with unresectable, stage IIIc/IVM1 NRAS-mutated cutaneous melanoma were randomized 2:1 to pimasertib (60 mg; oral twice-daily) or DTIC (1000 mg/m²; intravenously) on Day 1 of each 21-day cycle. Patients progressing on DTIC could crossover to pimasertib. Primary endpoint: investigator-assessed progression-free survival (PFS); secondary endpoints: overall survival (OS), objective response rate (ORR), quality of life (QoL), and safety. Overall, 194 patients were randomized (pimasertib n = 130, DTIC n = 64), and 191 received treatment (pimasertib n = 130, DTIC n = 61). PFS was significantly improved with pimasertib versus DTIC (median 13 versus 7 weeks, respectively; hazard ratio (HR) 0.59, 95% confidence interval (CI) 0.42–0.83; p = 0.0022). ORR was improved with pimasertib (odds ratio 2.24, 95% CI 1.00–4.98; p = 0.0453). OS was similar between treatments (median 9 versus 11 months, respectively; HR 0.89, 95% CI 0.61–1.30); 64% of patients receiving DTIC crossed over to pimasertib. Serious adverse events (AEs) were more frequent for pimasertib (57%) than DTIC (20%). The most common treatment-emergent AEs were diarrhea (82%) and blood creatine phosphokinase (CPK) increase (68%) for pimasertib, and nausea (41%) and fatigue (38%) for DTIC. Most frequent grade ≥3 AEs were CPK increase (34%) for pimasertib and neutropenia (15%) for DTIC. Mean QoL scores (baseline and last assessment) were similar between treatments. Pimasertib has activity in NRAS-mutated cutaneous melanoma and a safety profile consistent with known toxicities of MEK inhibitors. Trial registration: ClinicalTrials.gov, NCT01693068. Full article

(This article belongs to the Special Issue Targeted Therapies for Melanoma)

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11 pages, 826 KiB

Open AccessArticle

Combined Therapy with Anti-PD1 and BRAF and/or MEK Inhibitor for Advanced Melanoma: A Multicenter Cohort Study

by Sandra Huynh, Laurent Mortier, Caroline Dutriaux, Eve Maubec, Marie Boileau, Olivier Dereure, Marie-Therese Leccia, Jean-Philippe Arnault, Florence Brunet-Possenti, Francois Aubin, Brigitte Dreno, Marie Beylot-Barry, Celeste Lebbe, Wendy Lefevre and Julie Delyon

Cancers 2020, 12(6), 1666; https://doi.org/10.3390/cancers12061666 - 23 Jun 2020

Cited by 20 | Viewed by 3288

Abstract

Despite significant progress in melanoma survival, therapeutic options are still needed in case of progression under immune checkpoint inhibitors (ICI), and resistance to targeted therapies (TT) in BRAF-mutated melanomas. This study aimed to assess the safety of combined ICI and TT as a [...] Read more.

Despite significant progress in melanoma survival, therapeutic options are still needed in case of progression under immune checkpoint inhibitors (ICI), and resistance to targeted therapies (TT) in BRAF-mutated melanomas. This study aimed to assess the safety of combined ICI and TT as a rescue line in real-life clinical practice. We conducted a study within the prospective French multicentric MelBase cohort, including patients treated with a combination of anti-PD1 (pembrolizumab/nivolumab) and BRAF inhibitor (BRAFi: dabrafenib/vemurafenib) and/or MEK inhibitors (MEKi: trametinib/cobimetinib) for BRAF mutated or wild-type advanced melanoma. Fifty-nine patients were included: 30% received the triple combination, 34% an anti-PD1 and BRAFi, and 36% an anti-PD1 and MEKi. Grade 3–4 adverse events occurred in 12% of patients. Permanent discontinuation or dose reduction of one of the treatments for toxicity was reported in 14% and 7% of patients, respectively. In the BRAF wild-type subgroup, treatment with MEKi and anti-PD1 induced a tumor control rate of 83% and median progression-free survival of 7.1 months. The combination of anti-PD1 and BRAFi and/or MEKi was a safe rescue line for advanced melanoma patients previously treated with ICI/TT. The benefit of these combinations, specifically anti-PD1 and MEKi in BRAF wild-type melanoma patients, needs to be prospectively studied. Full article

(This article belongs to the Special Issue Targeted Therapies for Melanoma)

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24 pages, 4333 KiB

Open AccessArticle

Dual Targeting of BRAF and mTOR Signaling in Melanoma Cells with Pyridinyl Imidazole Compounds

by Veronika Palušová, Tereza Renzová, Amandine Verlande, Tereza Vaclová, Michaela Medková, Linda Cetlová, Miroslava Sedláčková, Hana Hříbková, Iva Slaninová, Miriama Krutá, Vladimír Rotrekl, Hana Uhlířová, Aneta Křížová, Radim Chmelík, Pavel Veselý, Michaela Krafčíková, Lukáš Trantírek, Kay Oliver Schink and Stjepan Uldrijan

Cancers 2020, 12(6), 1516; https://doi.org/10.3390/cancers12061516 - 10 Jun 2020

Cited by 11 | Viewed by 4764

Abstract

BRAF inhibitors can delay the progression of metastatic melanoma, but resistance usually emerges, leading to relapse. Drugs simultaneously targeting two or more pathways essential for cancer growth could slow or prevent the development of resistant clones. Here, we identified pyridinyl imidazole compounds SB202190, [...] Read more.

BRAF inhibitors can delay the progression of metastatic melanoma, but resistance usually emerges, leading to relapse. Drugs simultaneously targeting two or more pathways essential for cancer growth could slow or prevent the development of resistant clones. Here, we identified pyridinyl imidazole compounds SB202190, SB203580, and SB590885 as dual inhibitors of critical proliferative pathways in human melanoma cells bearing the V600E activating mutation of BRAF kinase. We found that the drugs simultaneously disrupt the BRAF V600E-driven extracellular signal-regulated kinase (ERK) mitogen-activated protein kinase (MAPK) activity and the mechanistic target of rapamycin complex 1 (mTORC1) signaling in melanoma cells. Pyridinyl imidazole compounds directly inhibit BRAF V600E kinase. Moreover, they interfere with the endolysosomal compartment, promoting the accumulation of large acidic vacuole-like vesicles and dynamic changes in mTOR signaling. A transient increase in mTORC1 activity is followed by the enrichment of the Ragulator complex protein p18/LAMTOR1 at contact sites of large vesicles and delocalization of mTOR from the lysosomes. The induced disruption of the endolysosomal pathway not only disrupts mTORC1 signaling, but also renders melanoma cells sensitive to endoplasmic reticulum (ER) stress. Our findings identify new activities of pharmacologically relevant small molecule compounds and provide a biological rationale for the development of anti-melanoma therapeutics based on the pyridinyl imidazole core. Full article

(This article belongs to the Special Issue Targeted Therapies for Melanoma)

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22 pages, 6503 KiB

Open AccessArticle

RKIP Regulates Differentiation-Related Features in Melanocytic Cells

by Cristina Penas, Aintzane Apraiz, Iraia Muñoa, Yoana Arroyo-Berdugo, Javier Rasero, Pilar A. Ezkurra, Veronica Velasco, Nerea Subiran, Anja K. Bosserhoff, Santos Alonso, Aintzane Asumendi and Maria D. Boyano

Cancers 2020, 12(6), 1451; https://doi.org/10.3390/cancers12061451 - 3 Jun 2020

Cited by 8 | Viewed by 3214

Abstract

Raf Kinase Inhibitor Protein (RKIP) has been extensively reported as an inhibitor of key signaling pathways involved in the aggressive tumor phenotype and shows decreased expression in several types of cancers. However, little is known about RKIP in melanoma or regarding its function [...] Read more.

Raf Kinase Inhibitor Protein (RKIP) has been extensively reported as an inhibitor of key signaling pathways involved in the aggressive tumor phenotype and shows decreased expression in several types of cancers. However, little is known about RKIP in melanoma or regarding its function in normal cells. We examined the role of RKIP in both primary melanocytes and malignant melanoma cells and evaluated its diagnostic and prognostic value. IHC analysis revealed a significantly higher expression of RKIP in nevi compared with early-stage (stage I–II, AJCC 8th) melanoma biopsies. Proliferation, wound healing, and collagen-coated transwell assays uncovered the implication of RKIP on the motility but not on the proliferative capacity of melanoma cells as RKIP protein levels were inversely correlated with the migration capacity of both primary and metastatic melanoma cells but did not alter other parameters. As shown by RNA sequencing, endogenous RKIP knockdown in primary melanocytes triggered the deregulation of cellular differentiation-related processes, including genes (i.e., ZEB1, THY-1) closely related to the EMT. Interestingly, NANOG was identified as a putative transcriptional regulator of many of the deregulated genes, and RKIP was able to decrease the activation of the NANOG promoter. As a whole, our data support the utility of RKIP as a diagnostic marker for early-stage melanomas. In addition, these findings indicate its participation in the maintenance of a differentiated state of melanocytic cells by modulating genes intimately linked to the cellular motility and explain the progressive decrease of RKIP often described in tumors. Full article

(This article belongs to the Special Issue Targeted Therapies for Melanoma)

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14 pages, 3358 KiB

Open AccessFeature PaperArticle

FGF2 Induces Resistance to Nilotinib through MAPK Pathway Activation in KIT Mutated Melanoma

by Pauline Tétu, Julie Delyon, Jocelyne André, Coralie Reger de Moura, Malak Sabbah, Ghanem E Ghanem, Maxime Battistella, Samia Mourah, Céleste Lebbé and Nicolas Dumaz

Cancers 2020, 12(5), 1062; https://doi.org/10.3390/cancers12051062 - 25 Apr 2020

Cited by 7 | Viewed by 2779

Abstract

KIT is a bona fide oncogene in a subset of melanoma and, ex vivo, KIT inhibitors are very efficient at killing KIT-mutant melanoma cell lines. However, KIT-mutant melanoma tumors tend to show a de novo resistance in most cases and a limited duration [...] Read more.

KIT is a bona fide oncogene in a subset of melanoma and, ex vivo, KIT inhibitors are very efficient at killing KIT-mutant melanoma cell lines. However, KIT-mutant melanoma tumors tend to show a de novo resistance in most cases and a limited duration of response when response is achieved. We performed pharmacodynamic studies on patients with KIT-mutated melanoma treated with nilotinib, which suggested that the FGF2 axis may be a mechanism of resistance in this subset of melanoma. Using several melanoma cell lines, which are dependent on oncogenic KIT, we showed that although KIT inhibition markedly decreased cell viability in melanoma cell lines with distinct KIT mutations, this effect was lessened in the presence of FGF2 due to inhibition of BIM expression by MAPK pathway activation. Addition of a MEK inhibitor reversed the FGF2-driven resistance for all KIT mutants. We confirmed the expression of FGF2 and activation of MEK-ERK in melanoma patients using in situ data from a clinical trial. Therefore, the combined inhibition of KIT with FGFR or MEK may be a next-step effective clinical strategy in KIT-mutant melanoma. Full article

(This article belongs to the Special Issue Targeted Therapies for Melanoma)

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11 pages, 913 KiB

Open AccessArticle

TERT Promoter Mutations Differently Correlate with the Clinical Outcome of MAPK Inhibitor-Treated Melanoma Patients

by Paola Del Bianco, Camilla Stagni, Silvia Giunco, Alessio Fabozzi, Lisa Elefanti, Stefania Pellegrini, Antonella Vecchiato, Jacopo Pigozzo, Carolina Zamuner, Anita De Rossi, Arcangela De Nicolo and Chiara Menin

Cancers 2020, 12(4), 946; https://doi.org/10.3390/cancers12040946 - 11 Apr 2020

Cited by 16 | Viewed by 3302

Abstract

Resistance is a major challenge in the management of mitogen-activated protein kinase inhibitor (MAPKi)-treated metastatic melanoma. Tumor genetic alterations can cause MAPK pathway reactivation, leading to lack of response and poor outcome. Characterization of the mutational profile in patients with melanoma might be [...] Read more.

Resistance is a major challenge in the management of mitogen-activated protein kinase inhibitor (MAPKi)-treated metastatic melanoma. Tumor genetic alterations can cause MAPK pathway reactivation, leading to lack of response and poor outcome. Characterization of the mutational profile in patients with melanoma might be crucial for patient-tailored treatment choices. Mutations in the promoter region of the telomerase reverse transcriptase gene (TERTprom) lead to increased TERT expression and telomerase activity and are frequent in BRAF^V600 mutant melanoma. Reportedly, TERTprom, and BRAF^V600 mutations cooperate in driving cancer progression and aggressiveness. We evaluated the effect of the TERTprom status on the clinical outcome in 97 MAPKi-treated melanoma patients. We observed that patients with the c.-146C > T mutation showed a significantly worse progression-free survival (PFS) compared to those carrying the c.-124C > T mutation and a two-fold increased risk of progression (median 5.4 vs. 9.5 months; hazard ratio (HR) 1.9; 95% confidence interval (CI) 1.2–3.2; p = 0.013). This trend was also observed for the overall survival (OS); melanoma patients with the c.-146C > T mutation showed a poorer prognosis compared to those with the c.-124C > T mutation (median 13.3 vs. 25.5 months; HR 1.9, 95% CI 1.1–3.3, p = 0.023). Our results disclose a different correlation of the two TERTprom mutations with MAPKi-treated melanoma patient outcome, highlighting a different impact of the pathway blockade. Full article

(This article belongs to the Special Issue Targeted Therapies for Melanoma)

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19 pages, 2034 KiB

Open AccessArticle

Population Pharmacokinetics/Pharmacodynamics of Dabrafenib Plus Trametinib in Patients with BRAF-Mutated Metastatic Melanoma

by David Balakirouchenane, Sarah Guégan, Chantal Csajka, Anne Jouinot, Valentine Heidelberger, Alicja Puszkiel, Ouidad Zehou, Nihel Khoudour, Perrine Courlet, Nora Kramkimel, Coralie Lheure, Nathalie Franck, Olivier Huillard, Jennifer Arrondeau, Michel Vidal, Francois Goldwasser, Eve Maubec, Nicolas Dupin, Selim Aractingi, Monia Guidi and Benoit Blanchet Show full author list Hide full author list

Cancers 2020, 12(4), 931; https://doi.org/10.3390/cancers12040931 - 9 Apr 2020

Cited by 17 | Viewed by 4107

Abstract

Patients treated with dabrafenib/trametinib (DAB/TRA) exhibit a large interindividual variability in clinical outcomes. The aims of this study were to characterize the pharmacokinetics of DAB, hydroxy-dabrafenib (OHD), and TRA in BRAF-mutated patients and to investigate the exposure–response relationship for toxicity and efficacy in [...] Read more.

Patients treated with dabrafenib/trametinib (DAB/TRA) exhibit a large interindividual variability in clinical outcomes. The aims of this study were to characterize the pharmacokinetics of DAB, hydroxy-dabrafenib (OHD), and TRA in BRAF-mutated patients and to investigate the exposure–response relationship for toxicity and efficacy in metastatic melanoma (MM) patients. Univariate Fisher and Wilcoxon models including drug systemic exposure (area under the plasma concentration curve, AUC) were used to identify prognostic factors for the onset of dose-limiting toxicities (DLT), and Cox models for overall (OS) and progression-free survival (PFS). Seventy-three BRAF-mutated patients were included in pharmacokinetic (n = 424, NONMEM) and 52 in pharmacokinetic/pharmacodynamic analyses. Age and sex were identified as determinants of DAB and OHD clearances (p < 0.01). MM patients experiencing DLT were overexposed to DAB compared to patients without DLT (AUC: 9624 vs. 7485 ng∙h/mL, respectively, p < 0.01). Eastern Cooperative Oncology Group Performance Status (ECOG PS) ≥ 2 and plasma ratio AUC_OHD/AUC_DAB ≥ 1 were independently associated with shorter OS (HR: 6.58 (1.29–33.56); p = 0.023 and 10.61 (2.34–48.15), p = 0.022, respectively). A number of metastatic sites ≥3 and cerebral metastases were associated with shorter PFS (HR = 3.25 (1.11–9.50); p = 0.032 and HR = 1.23 (1.35–10.39), p = 0.011; respectively). TRA plasma exposure was neither associated with toxicity nor efficacy. Our results suggest that early drug monitoring could be helpful to prevent the onset of DLT in MM patients, especially in fragile patients such as the elderly. Regarding efficacy, the clinical benefit to monitor plasma ratio AUC_OHD/AUC_DAB deserves more investigation in a larger cohort of MM patients. Full article

(This article belongs to the Special Issue Targeted Therapies for Melanoma)

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0 pages, 8770 KiB

Open AccessArticle

Kinome Profiling to Predict Sensitivity to MAPK Inhibition in Melanoma and to Provide New Insights into Intrinsic and Acquired Mechanism of Resistance

by Mohammad Krayem, Philippe Aftimos, Ahmad Najem, Tim van den Hooven, Adriënne van den Berg, Liesbeth Hovestad-Bijl, Rik de Wijn, Riet Hilhorst, Rob Ruijtenbeek, Malak Sabbah, Joseph Kerger, Ahmad Awada, Fabrice Journe and Ghanem E. Ghanem

Cancers 2020, 12(2), 512; https://doi.org/10.3390/cancers12020512 - 22 Feb 2020

Cited by 18 | Viewed by 4623 | Correction

Abstract

Mitogen-activated protein kinase (MAPK) inhibition with the combination of BRAF (Rapidly Accelerated Fibrosarcoma) and MEK (Mitogen-activated protein kinase kinase) inhibitors has become the standard of first-line therapy of metastatic melanoma harbouring BRAF V600 mutations. However, about half of the patients present with primary [...] Read more.

Mitogen-activated protein kinase (MAPK) inhibition with the combination of BRAF (Rapidly Accelerated Fibrosarcoma) and MEK (Mitogen-activated protein kinase kinase) inhibitors has become the standard of first-line therapy of metastatic melanoma harbouring BRAF V600 mutations. However, about half of the patients present with primary resistance while the remaining develop secondary resistance under prolonged treatment. Thus, there is a need for predictive biomarkers for sensitivity and/or resistance to further refine the patient population likely to benefit from MAPK inhibitors. In this study, we explored a top-down approach using a multiplex kinase assay, first, to discover a kinome signature predicting sensitivity, intrinsic and acquired resistance to MAPK inhibitors in melanoma, and second, to understand the mechanism of resistance using cell lines. Pre-dose tissues from patients (four responders and three non-responders to BRAFi monotherapy) were profiled for phosphotyrosine kinase (PTK) and serine-threonine kinase (STK) activities on a PamChip^® peptide microarray in the presence and absence of ex vivo BRAFi. In addition, molecular studies were conducted on four sensitive parental lines, their offspring with acquired resistance to BRAFi and two lines with intrinsic resistance. PTK and STK activities in cell lysates were measured in the presence and absence of ex vivo BRAFi and/or MEKi. In tissue lysates, concentration-dependent ex vivo inhibition of STK and PTK activities with dabrafenib was stronger in responders than in non-responders. This difference was confirmed in cell lines comparing sensitive and resistant ones. Interestingly, common features of resistance were increased activity of receptor tyrosine kinases, Proto-oncogene tyrosine-protein kinase Src (Src) family kinases and protein kinase B (PKB, AKT) signalling. These latter results were confirmed by Western blots. While dabrafenib alone showed an inhibition of STK and PTK activities in both tissues and cell lines, the combination of dabrafenib and trametinib showed an antagonism on the STK activities and a synergism on PTK activities, resulting in stronger inhibitions of overall tyrosine kinase activities. Altogether; these data reveal that resistance of tumours and cell lines to MAPK inhibitors can be predicted using a multiplex kinase assay and is associated with an increase in specific tyrosine kinase activities and globally to AKT signalling in the patient’s tissue. Thus, such a predictive kinome signature would help to identify patients with innate resistance to MAPK double inhibition in order to propose other therapies. Full article

(This article belongs to the Special Issue Targeted Therapies for Melanoma)

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16 pages, 2846 KiB

Open AccessArticle

ErbB3 Phosphorylation as Central Event in Adaptive Resistance to Targeted Therapy in Metastatic Melanoma: Early Detection in CTCs during Therapy and Insights into Regulation by Autocrine Neuregulin

by Ciro Francesco Ruggiero, Debora Malpicci, Luigi Fattore, Gabriele Madonna, Vito Vanella, Domenico Mallardo, Domenico Liguoro, Valentina Salvati, Mariaelena Capone, Barbara Bedogni, Paolo Antonio Ascierto, Rita Mancini and Gennaro Ciliberto

Cancers 2019, 11(10), 1425; https://doi.org/10.3390/cancers11101425 - 25 Sep 2019

Cited by 23 | Viewed by 3800

Abstract

In recent years the introduction of target therapies with BRAF and MEK inhibitors (MAPKi) and of immunotherapy with anti-CTLA-4 and anti-PD-1 monoclonal antibodies have dramatically improved survival of metastatic melanoma patients. Despite these changes drug resistance remains a major hurdle. Several mechanisms are [...] Read more.

In recent years the introduction of target therapies with BRAF and MEK inhibitors (MAPKi) and of immunotherapy with anti-CTLA-4 and anti-PD-1 monoclonal antibodies have dramatically improved survival of metastatic melanoma patients. Despite these changes drug resistance remains a major hurdle. Several mechanisms are at the basis of drug resistance. Particular attention has been devoted over the last years to unravel mechanisms at the basis of adaptive/non genetic resistance occurring in BRAF mutated melanomas upon treatment with to MAPKi. In this paper we focus on the involvement of activation of ErbB3 receptor following early exposure of melanoma cells to BRAF or MEK inhibitors, and the following induction of PI3K/AKT pathway. Although different mechanisms have been invoked in the past at the basis of this activation we show here with a combination of approaches that autocrine production of neuregulin by melanoma cells is a major factor responsible for ErbB3 phosphorylation and downstream AKT activation. Interestingly the kinetic of neuregulin production and of the ensuing ErbB3 phosphorylation is different in different melanoma cell lines which underscores the high degree of tumor heterogeneity. Moreover, heterogeneity is further highlighted by the evidence that in different cell lines neuregulin upregulation can occur at the transcriptional or at the post-transcritpional level. Finally we complement our study by showing with a liquid biopsy assay that circulating tumor cells (CTCs) from melanoma patients undergo upregulation of ErbB3 phosphorylation in vivo shortly after initiation of therapy. Full article

(This article belongs to the Special Issue Targeted Therapies for Melanoma)

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Review

Jump to: Editorial, Research, Other

20 pages, 355 KiB

Open AccessReview

Melanoma Brain Metastases in the Era of Target Therapies: An Overview

by Paolo Becco, Susanna Gallo, Stefano Poletto, Mirko Pio Manlio Frascione, Luca Crotto, Alessandro Zaccagna, Luca Paruzzo, Daniela Caravelli, Fabrizio Carnevale-Schianca and Massimo Aglietta

Cancers 2020, 12(6), 1640; https://doi.org/10.3390/cancers12061640 - 21 Jun 2020

Cited by 27 | Viewed by 5705

Abstract

Malignant melanoma is the third most common type of tumor that causes brain metastases. Patients with cerebral involvement have a dismal prognosis and their treatment is an unmet medical need. Brain involvement is a multistep process involving several signaling pathways such as Janus [...] Read more.

Malignant melanoma is the third most common type of tumor that causes brain metastases. Patients with cerebral involvement have a dismal prognosis and their treatment is an unmet medical need. Brain involvement is a multistep process involving several signaling pathways such as Janus kinase/signal Transducer and Activator of Transcription (JAK/STAT), Phosphoinositide 3-kinase/Protein Kinase B (PI3K/AKT), Vascular Endothelial Growth Factor and Phosphatase and Tensin Homolog (PTEN). Recently therapy that targets the MAPK signaling (BRAF/MEK inhibitors) and immunotherapy (anti-CTLA4 and anti-PD1 agents) have changed the therapeutic approaches to stage IV melanoma. In contrast, there are no solid data about patients with brain metastases, who are usually excluded from clinical trials. Retrospective data showed that BRAF-inhibitors, alone or in combination with MEK-inhibitors have interesting clinical activity in this setting. Prospective data about the combinations of BRAF/MEK inhibitors have been recently published, showing an improved overall response rate. Short intracranial disease control is still a challenge. Several attempts have been made in order to improve it with combinations between local and systemic therapies. Immunotherapy approaches seem to retain promising activity in the treatment of melanoma brain metastasis as showed by the results of clinical trials investigating the combination of anti-CTL4 (Ipilimumab) and anti-PD1(Nivolumab). Studies about the combination or the sequential approach of target therapy and immunotherapy are ongoing, with immature results. Several clinical trials are ongoing trying to explore new approaches in order to overcome tumor resistance. At this moment the correct therapeutic choices for melanoma with intracranial involvement is still a challenge and new strategies are needed. Full article

(This article belongs to the Special Issue Targeted Therapies for Melanoma)

20 pages, 1485 KiB

Open AccessReview

Bad Neighborhood: Fibrotic Stroma as a New Player in Melanoma Resistance to Targeted Therapies

by Serena Diazzi, Sophie Tartare-Deckert and Marcel Deckert

Cancers 2020, 12(6), 1364; https://doi.org/10.3390/cancers12061364 - 26 May 2020

Cited by 18 | Viewed by 5081

Abstract

Current treatments for metastatic cutaneous melanoma include immunotherapies and drugs targeting key molecules of the mitogen-activated protein kinase (MAPK) pathway, which is often activated by BRAF driver mutations. Overall responses from patients with metastatic BRAF mutant melanoma are better with therapies combining BRAF [...] Read more.

Current treatments for metastatic cutaneous melanoma include immunotherapies and drugs targeting key molecules of the mitogen-activated protein kinase (MAPK) pathway, which is often activated by BRAF driver mutations. Overall responses from patients with metastatic BRAF mutant melanoma are better with therapies combining BRAF and mitogen-activated protein kinase kinase (MEK) inhibitors. However, most patients that initially respond to therapies develop drug resistance within months. Acquired resistance to targeted therapies can be due to additional genetic alterations in melanoma cells and to non-genetic events frequently associated with transcriptional reprogramming and a dedifferentiated cell state. In this second scenario, it is possible to identify pro-fibrotic responses induced by targeted therapies that contribute to the alteration of the melanoma tumor microenvironment. A close interrelationship between chronic fibrosis and cancer has been established for several malignancies including breast and pancreatic cancers. In this context, the contribution of fibrosis to drug adaptation and therapy resistance in melanoma is rapidly emerging. In this review, we summarize recent evidence underlining the hallmarks of fibrotic diseases in drug-exposed and resistant melanoma, including increased remodeling of the extracellular matrix, enhanced actin cytoskeleton plasticity, high sensitivity to mechanical cues, and the establishment of an inflammatory microenvironment. We also discuss several potential therapeutic options for manipulating this fibrotic-like response to combat drug-resistant and invasive melanoma. Full article

(This article belongs to the Special Issue Targeted Therapies for Melanoma)

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16 pages, 1937 KiB

Open AccessReview

Efficacy and Adverse Events in Metastatic Melanoma Patients Treated with Combination BRAF Plus MEK Inhibitors Versus BRAF Inhibitors: A Systematic Review

by Austin Greco, Danish Safi, Umang Swami, Tim Ginader, Mohammed Milhem and Yousef Zakharia

Cancers 2019, 11(12), 1950; https://doi.org/10.3390/cancers11121950 - 5 Dec 2019

Cited by 24 | Viewed by 3692

Abstract

We reviewed the literature to assess the efficacy and risk of constitutional, cardiac, gastrointestinal, and dermatological toxicities of combined BRAF plus MEK inhibitors versus BRAF inhibitors alone in patients with metastatic melanoma with BRAF mutations. Searches were conducted in PubMed, Cochrane Database of [...] Read more.

We reviewed the literature to assess the efficacy and risk of constitutional, cardiac, gastrointestinal, and dermatological toxicities of combined BRAF plus MEK inhibitors versus BRAF inhibitors alone in patients with metastatic melanoma with BRAF mutations. Searches were conducted in PubMed, Cochrane Database of Systematic Reviews, Google scholar, ASCO, Scopus, and EMBASE for reports published from January 2010 through March 2019. Efficacy, including progression-free survival (PFS) and overall survival (OS) rates, were assessed by hazard ratio (HR); objective response rates (ORR) were assessed by odds ratio (OR). The randomized clinical trials (RCTs) with comparison to vemurafenib monotherapy were included to determine constitutional, gastrointestinal, cardiac, and dermatological toxicities using PRISMA statistical analysis with relative risk (RR) for equal comparison to avoid inclusion bias. Five RTCs comprising 2307 patients were included to assess efficacy, while three of the five RCTs comprising 1776 patients were included to assess adverse events. BRAF plus MEK inhibitor combination therapy demonstrated overall better efficacy compared to BRAF inhibitor monotherapy. Combination therapies appear to have favorable dermatologic side effect profiles, similar constitutional and cardiac profiles, and slightly worse gastrointestinal profiles compares to monotherapy regimens. Full article

(This article belongs to the Special Issue Targeted Therapies for Melanoma)

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2 pages, 183 KiB

Open AccessErratum

Erratum: Krayem, M., et al. Kinome Profiling to Predict Sensitivity to MAPK Inhibition in Melanoma and to Provide New Insights into Intrinsic and Acquired Mechanism of Resistance Short Title: Sensitivity Prediction to MAPK Inhibitors in Melanoma. Cancers 2020, 12, 512

by Mohammad Krayem, Philippe Aftimos, Ahmad Najem, Tim van den Hooven, Adriënne van den Berg, Liesbeth Hovestad-Bijl, Rik de Wijn, Riet Hilhorst, Rob Ruijtenbeek, Malak Sabbah, Joseph Kerger, Ahmad Awada, Fabrice Journe and Ghanem E. Ghanem

Cancers 2020, 12(10), 2981; https://doi.org/10.3390/cancers12102981 - 14 Oct 2020

Cited by 1 | Viewed by 1561

Abstract

The authors would like to make a correction to their published paper [...] Full article

(This article belongs to the Special Issue Targeted Therapies for Melanoma)

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