Cancers

19 pages, 1476 KiB

Open AccessEditor’s ChoiceReview

Molecular Targeting Therapy against EGFR Family in Breast Cancer: Progress and Future Potentials

by Amaia Eleonora Maennling^1,†, Mehmet Kemal Tur^2,3,†

, Marcus Niebert⁴, Torsten Klockenbring⁵

, Felix Zeppernick⁶, Stefan Gattenlöhner², Ivo Meinhold-Heerlein⁶ and Ahmad Fawzi Hussain^6,*

¹ Department of Gynecology and Obstetrics, University Hospital RWTH Aachen, Pauwelsstrasse 30, 52074 Aachen, Germany

² Institute of Pathology, University Hospital Giessen, Justus-Liebig-University Giessen, Langhanssstr. 10, 35392 Giessen, Germany

³ Department of Pharmacology and Personalised Medicine, Faculty of Health, Medicine and Life Science, Maastricht University, Universiteitssingel 40, 6229 MD Maastricht, The Netherlands

⁴ Department of Molecular Cytology and Functional Genomics, Institute of Pathology, University Hospital Giessen, Justus-Liebig-University Giessen, Langhanssstr. 10, 35392 Giessen, Germany

⁵ Department of Biological Sensing and Detection, Fraunhofer Institute for Molecular Biology and Applied Ecology IME, Forckenbeckstrasse 6, 52074 Aachen, Germany

⁶ Department of Gynecology and Obstetrics, Medical Faculty, Justus-Liebig-University Giessen, Klinikstr. 33, 35392 Giessen, Germany

^† These authors contributed equally to this work.

Cancers 2019, 11(12), 1826; https://doi.org/10.3390/cancers11121826 - 20 Nov 2019

Cited by 176 | Viewed by 14339

Abstract

The epidermal growth factor receptor (EGFR) family contains four transmembrane tyrosine kinases (EGFR1/ErbB1, Her2/ErbB2, Her3/ErbB3 and Her4/ErbB4) and 13 secreted polypeptide ligands. EGFRs are overexpressed in many solid tumors, including breast, pancreas, head-and-neck, prostate, ovarian, renal, colon, and non-small-cell lung cancer. Such overexpression [...] Read more.

The epidermal growth factor receptor (EGFR) family contains four transmembrane tyrosine kinases (EGFR1/ErbB1, Her2/ErbB2, Her3/ErbB3 and Her4/ErbB4) and 13 secreted polypeptide ligands. EGFRs are overexpressed in many solid tumors, including breast, pancreas, head-and-neck, prostate, ovarian, renal, colon, and non-small-cell lung cancer. Such overexpression produces strong stimulation of downstream signaling pathways, which induce cell growth, cell differentiation, cell cycle progression, angiogenesis, cell motility and blocking of apoptosis.The high expression and/or functional activation of EGFRs correlates with the pathogenesis and progression of several cancers, which make them attractive targets for both diagnosis and therapy. Several approaches have been developed to target these receptors and/or the EGFR modulated effects in cancer cells. Most approaches include the development of anti-EGFRs antibodies and/or small-molecule EGFR inhibitors. This review presents the state-of-the-art and future prospects of targeting EGFRs to treat breast cancer. Full article

(This article belongs to the Special Issue Epidermal Growth Factor Receptor Signaling in Cancer)

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10 pages, 825 KiB

Open AccessArticle

Liquid Biopsy Testing Can Improve Selection of Advanced Non-Small-Cell Lung Cancer Patients to Rechallenge with Gefitinib

by Riziero Esposito Abate^1,†

, Raffaella Pasquale^1,†, Alessandra Sacco¹, Maria Carmela Piccirillo², Alessandro Morabito³, Paolo Bidoli⁴, Giovanna Finocchiaro⁵, Rita Chiari⁶, Luisa Foltran⁷, Roberta Buosi⁸, Marcello Tiseo⁹

, Laura Giannetta¹⁰, Ciro Battiloro¹¹, Gianpiero Fasola¹²

, Gianpiero Romano¹³, Libero Ciuffreda¹⁴, Antonio Frassoldati¹⁵, Filippo de Marinis¹⁶

, Federico Cappuzzo¹⁷ and Nicola Normanno^1,*

¹ Cell Biology and Biotherapy Unit, Istiuto Nazionale Tumori “Fondazione G. Pascale”-IRCCS, 80131 Naples, Italy

² Clinical Trials Unit, Istituto Nazionale Tumori, IRCCS-Fondazione G. Pascale, 80131 Napoli, Italy

³ Medical Oncology, Thoracic Department, Istiuto Nazionale Tumori “Fondazione G. Pascale”-IRCCS, 80131 Napoli, Italy

⁴ Department of Oncology, Azienda Socio Sanitaria Territoriale (ASST) Monza, Presidio San Gerardo, 20900 Monza, Italy

⁵ Department of Oncology & Hematology, Humanitas Clinical & Research Center, 20089 Rozzano (MI), Italy

⁶ Medical Oncology, Santa Maria della Misericordia Hospital, Azienda Ospedaliera di Perugia, University of Perugia, 06129 Perugia, Italy

⁷ Department of Medical Oncology, Centro di Riferimento Oncologico di Aviano (CRO), IRCSS, 33081 Aviano, Italy

⁸ Department of Medical Oncology, Ospedale Santo Spirito, 15033 Casale Monferrato, Italy

⁹ Department of Medicine and Surgery, University of Parma, 43121 Parma, Italy

¹⁰ Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, 20162 Milan, Italy

¹¹ Division of Pulmonary Oncology, Azienda Ospedaliera Dei Colli Monaldi, 80131 Naples, Italy

¹² Azienda Ospedaliera Universitaria Santa Maria della Misericordia, 33100 Udine, Italy

¹³ Presidio Ospedaliero Vito Fazzi, 73100 Lecce, Italy

¹⁴ AOU Città della salute e della Scienza di Torino, 10126 Turin, Italy

¹⁵ Arcispedale S. Anna, Ferrara 44124, Italy

¹⁶ Division of Thoracic Oncology, European Institute of Oncology, IRCCS, 20122 Milan, Italy

¹⁷ Director Oncology and Hematology Department, AUSL Romagna, 48121 Ravenna, Italy

^† Both authors contributed equally to this work.

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Cancers 2019, 11(10), 1431; https://doi.org/10.3390/cancers11101431 - 25 Sep 2019

Cited by 11 | Viewed by 3555

Abstract

The ICARUS trial is a phase II, open label, multicenter, single arm study conducted to investigate the efficacy, safety, and tolerability of a rechallenge treatment with the first-generation tyrosine kinase inhibitor (TKI) gefitinib in advanced non-small-cell lung cancer (NSCLC) patients carrying activating mutations [...] Read more.

The ICARUS trial is a phase II, open label, multicenter, single arm study conducted to investigate the efficacy, safety, and tolerability of a rechallenge treatment with the first-generation tyrosine kinase inhibitor (TKI) gefitinib in advanced non-small-cell lung cancer (NSCLC) patients carrying activating mutations of the epidermal growth factor receptor (EGFR). The ICARUS trial enrolled 61 patients who were rechallenged with gefitinib at progression after second-line chemotherapy. Serum-derived circulating cell-free DNA (cfDNA) collected before the rechallenge from a cohort of 29 patients, was retrospectively analyzed for the EGFR exon 19 deletions and for the p.L858R and p.T790M single nucleotide variants (SNV). The analysis of cfDNA detected the same EGFR activating mutation reported in the tumor tissue in 20/29 patients, with a sensitivity of 69%. Moreover, a p.T790M variant was found in 14/29 patients (48.3%). The median progression-free survival (PFS) was 2.7 months for p.T790M positive patients (CI 95% 1.4–3.1 months) versus 3.5 months for the p.T790M negative patients (CI 95% 1.6–5.3 months), resulting in a statistically significant difference (Long rank test p = 0.0180). These findings confirmed the role of the p.T790M mutation in the resistance to first-generation TKIs. More importantly, our data suggest that TKI rechallenge should be guided by biomarker testing. Full article

(This article belongs to the Special Issue Epidermal Growth Factor Receptor Signaling in Cancer)

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20 pages, 2902 KiB

Open AccessArticle

Macrophage Migration Inhibitory Factor Is a Molecular Determinant of the Anti-EGFR Monoclonal Antibody Cetuximab Resistance in Human Colorectal Cancer Cells

by Rosita Russo^1,†, Nunzia Matrone^2,†

, Valentina Belli², Davide Ciardiello²

, Mariangela Valletta¹, Sabrina Esposito¹

, Paolo Vincenzo Pedone¹, Fortunato Ciardiello², Teresa Troiani^2,*,‡ and Angela Chambery^1,*,‡

¹ Department of Environmental, Biological and Pharmaceutical Sciences and Technologies, Università degli studi della Campania “Luigi Vanvitelli”, 81100 Caserta, Italy

² Department of Precision Medicine, Università degli studi della Campania “Luigi Vanvitelli”, 80131 Naples, Italy

^† These authors share equal contribution.

^‡ These authors share equal senior authorship.

Cancers 2019, 11(10), 1430; https://doi.org/10.3390/cancers11101430 - 25 Sep 2019

Cited by 12 | Viewed by 4912

Abstract

Background: The clinical impact of the monoclonal antibody cetuximab targeting the EGFR in colorectal cancer (CRC) is widely recognized. Nevertheless, the onset of cetuximab resistance is a serious issue that limits the effectiveness of this drug in targeted therapies. Unraveling the molecular players [...] Read more.

Background: The clinical impact of the monoclonal antibody cetuximab targeting the EGFR in colorectal cancer (CRC) is widely recognized. Nevertheless, the onset of cetuximab resistance is a serious issue that limits the effectiveness of this drug in targeted therapies. Unraveling the molecular players involved in cancer resistance is the first step towards the identification of alternative signaling pathways that can be targeted to circumvent resistance mechanisms restoring the efficacy of therapeutic treatments in a tailored manner. Methods: By applying a nanoLC-MS/MS TMT isobaric labeling-based approach, we have delineated a molecular hallmark of cetuximab-resistance in CRC. Results: We identified macrophage migration inhibitory factor (MIF) as a molecular determinant capable of triggering cancer resistance in sensitive human CRC cells. Blocking the MIF axis in resistant cells by a selective MIF inhibitor restores cell sensitivity to cetuximab. The combined treatment with cetuximab and the MIF inhibitor further enhanced cell growth inhibition in CRC resistant cell lines with a synergistic effect depending on inhibition of key downstream effectors of the MAPK and AKT signaling pathways. Conclusions: Collectively, our results suggest the association of MIF signaling and its dysregulation to cetuximab drug resistance, paving the way to the development of personalized combination therapies targeting the MIF axis. Full article

(This article belongs to the Special Issue Epidermal Growth Factor Receptor Signaling in Cancer)

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15 pages, 1085 KiB

Open AccessEditor’s ChoiceReview

Tumour Microenvironment and Immune Evasion in EGFR Addicted NSCLC: Hurdles and Possibilities

by Antonio Santaniello^1,†, Fabiana Napolitano^1,†

, Alberto Servetto¹, Pietro De Placido¹, Nicola Silvestris^2,3, Cataldo Bianco⁴, Luigi Formisano^1,*

and Roberto Bianco^1,*

¹ Department of Clinical Medicine and Surgery, University of Naples “Federico II”, 80131 Naples, Italy

² Medical Oncology Unit, IRCCS Istituto Tumori “Giovanni Paolo II” of Bari, 70124 Bari, Italy

³ Department of Biomedical Science and Human Oncology, University of Bari “Aldo Moro”, 70124 Bari, Italy

⁴ Department of Experimental and Clinical Medicine, University of Catanzaro “Magna Graecia”, 88100 Catanzaro, Italy

^† Both authors equally contributed to the manuscript.

Cancers 2019, 11(10), 1419; https://doi.org/10.3390/cancers11101419 - 24 Sep 2019

Cited by 54 | Viewed by 7423

Abstract

In the last few years, the treatment strategy in Non-Small Cell Lung Cancer (NSCLC) patients has been heavily modified by the introduction of the immune-checkpoint inhibitors. Anti-programmed cell death 1/programmed cell death ligand 1 (PD-1/PD-L1) therapy has improved both progression-free and the overall [...] Read more.

In the last few years, the treatment strategy in Non-Small Cell Lung Cancer (NSCLC) patients has been heavily modified by the introduction of the immune-checkpoint inhibitors. Anti-programmed cell death 1/programmed cell death ligand 1 (PD-1/PD-L1) therapy has improved both progression-free and the overall survival in almost all subgroups of patients, with or without PDL1 expression, with different degrees of responses. However, there are patients that are not benefitting from this treatment. A defined group of immune-checkpoint inhibitors non-responder tumours carry EGFR (epidermal growth factor receptor) mutations: nowadays, anti-PD-1/PD-L1 clinical trials often do not involve this type of patient and the use of immune-checkpoint inhibitors are under evaluation in this setting. Our review aims to elucidate the mechanisms underlying this resistance: we focused on evaluating the role of the tumour microenvironment, including infiltrating cells, cytokines, secreted factors, and angiogenesis, and its interaction with the tumour tissue. Finally, we analysed the possible role of immunotherapy in EGFR mutated tumours. Full article

(This article belongs to the Special Issue Epidermal Growth Factor Receptor Signaling in Cancer)

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24 pages, 2929 KiB

Open AccessReview

Targeting Autophagy for Overcoming Resistance to Anti-EGFR Treatments

by Yoojung Kwon¹, Misun Kim¹, Hyun Suk Jung¹, Youngmi Kim² and Dooil Jeoung^1,*

¹ Department of Biochemistry, College of Natural Sciences, Kangwon National University, Chunchon 24341, Korea

² Institute of New Frontier Research, College of Medicine, Hallym University, Chunchon 24251, Korea

Cancers 2019, 11(9), 1374; https://doi.org/10.3390/cancers11091374 - 16 Sep 2019

Cited by 71 | Viewed by 9746

Abstract

Epidermal growth factor receptor (EGFR) plays critical roles in cell proliferation, tumorigenesis, and anti-cancer drug resistance. Overexpression and somatic mutations of EGFR result in enhanced cancer cell survival. Therefore, EGFR can be a target for the development of anti-cancer therapy. Patients with cancers, [...] Read more.

Epidermal growth factor receptor (EGFR) plays critical roles in cell proliferation, tumorigenesis, and anti-cancer drug resistance. Overexpression and somatic mutations of EGFR result in enhanced cancer cell survival. Therefore, EGFR can be a target for the development of anti-cancer therapy. Patients with cancers, including non-small cell lung cancers (NSCLC), have been shown to response to EGFR-tyrosine kinase inhibitors (EGFR-TKIs) and anti-EGFR antibodies. However, resistance to these anti-EGFR treatments has developed. Autophagy has emerged as a potential mechanism involved in the acquired resistance to anti-EGFR treatments. Anti-EGFR treatments can induce autophagy and result in resistance to anti-EGFR treatments. Autophagy is a programmed catabolic process stimulated by various stimuli. It promotes cellular survival under these stress conditions. Under normal conditions, EGFR-activated phosphoinositide 3-kinase (PI3K)/AKT serine/threonine kinase (AKT)/mammalian target of rapamycin (mTOR) signaling inhibits autophagy while EGFR/rat sarcoma viral oncogene homolog (RAS)/mitogen-activated protein kinase kinase (MEK)/mitogen-activated protein kinase (MAPK) signaling promotes autophagy. Thus, targeting autophagy may overcome resistance to anti-EGFR treatments. Inhibitors targeting autophagy and EGFR signaling have been under development. In this review, we discuss crosstalk between EGFR signaling and autophagy. We also assess whether autophagy inhibition, along with anti-EGFR treatments, might represent a promising approach to overcome resistance to anti-EGFR treatments in various cancers. In addition, we discuss new developments concerning anti-autophagy therapeutics for overcoming resistance to anti-EGFR treatments in various cancers. Full article

(This article belongs to the Special Issue Epidermal Growth Factor Receptor Signaling in Cancer)

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16 pages, 1211 KiB

Open AccessReview

Immune Resistance and EGFR Antagonists in Colorectal Cancer

by Guido Giordano¹, Andrea Remo²

, Almudena Porras^3,4,*

and Massimo Pancione^3,5,*

¹ U.O.C. Medical Oncology, Ospedali Riuniti, Azienda Ospedaliero Universitaria, 251 Foggia, Italy

² Pathology Unit, Mater Salutis Hospital AULSS9, “Scaligera”, 37122 Verona, Italy

³ Department of Biochemistry and Molecular Biology, Faculty of Pharmacy, Complutense University Madrid, 28040 Madrid, Spain

⁴ Health Research Institute of the Hospital Clínico San Carlos (IdISSC), 28040 Madrid, Spain

⁵ Department of Sciences and Technologies, University of Sannio, 82100 Benevento, Italy

Cancers 2019, 11(8), 1089; https://doi.org/10.3390/cancers11081089 - 31 Jul 2019

Cited by 39 | Viewed by 6645

Abstract

Targeting the epidermal growth factor receptor (EGFR) either alone or in combination with chemotherapy in patients with RAS wild type metastatic colorectal cancer (mCRC) has revolutionized the treatment of CRC, but with less results than initially envisaged. In recent years, the discovery of [...] Read more.

Targeting the epidermal growth factor receptor (EGFR) either alone or in combination with chemotherapy in patients with RAS wild type metastatic colorectal cancer (mCRC) has revolutionized the treatment of CRC, but with less results than initially envisaged. In recent years, the discovery of multiple pathways leading to the escape from anti-EGFR therapy has revealed an enormous complexity and heterogeneity of human CRC due to the intrinsic genomic instability and immune/cancer cell interaction. Therefore, understanding the mechanistic basis of acquired resistance to targeted therapies represents a major challenge to improve the clinical outcomes of patients with CRC. The latest findings strongly suggest that complex molecular alterations coupled with changes of the immune tumor microenvironment may substantially contribute to the clinical efficacy of EGFR antagonist. In this review, we discuss the most recent findings that contribute to both primary and acquired anti-EGFR therapy resistance. In addition, we analyze how strategies aiming to enhance the favorable effects in the tumor microenvironment may contribute to overcome resistance to EGFR therapies. Full article

(This article belongs to the Special Issue Epidermal Growth Factor Receptor Signaling in Cancer)

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13 pages, 1279 KiB

Open AccessReview

The d16HER2 Splice Variant: A Friend or Foe of HER2-Positive Cancers?

by Lorenzo Castagnoli¹, Michael Ladomery², Elda Tagliabue^1,†

and Serenella M. Pupa^1,*,†

¹ Molecular Targeting Unit, Department of Research, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133 Milan, Italy

² Faculty of Health and Applied Sciences, University of the West of England, Coldharbour Lane, Frenchay, Bristol BS16 1QY, UK

^† These authors contributed equally.

Cancers 2019, 11(7), 902; https://doi.org/10.3390/cancers11070902 - 28 Jun 2019

Cited by 29 | Viewed by 5590

Abstract

Human epidermal growth factor receptor 2 (ERBB2 or HER2) amplification/overexpression is associated with a particularly aggressive molecular subtype of breast cancer (BC), characterized by a poor prognosis, increased metastatic potential, and disease recurrence. As only approximately 50% of HER2-positive patients respond to [...] Read more.

Human epidermal growth factor receptor 2 (ERBB2 or HER2) amplification/overexpression is associated with a particularly aggressive molecular subtype of breast cancer (BC), characterized by a poor prognosis, increased metastatic potential, and disease recurrence. As only approximately 50% of HER2-positive patients respond to HER2-targeted therapies, greater knowledge of the biology of HER2 and the mechanisms that underlie drug susceptibility is needed to improve cure rates. Evidence suggests that the coexistence of full-length, wild-type HER2 (wtHER2) and altered forms of HER2—such as carboxy-terminus-truncated fragments, activating mutations, and splice variants—significantly increases the heterogeneity of HER2-positive disease, affecting its biology, clinical course, and treatment response. In particular, expression of the d16HER2 splice variant in human HER2-positive BC has a crucial pathobiological function, wherein the absence of sixteen amino acids from the extracellular domain induces the formation of stable and constitutively active HER2 homodimers on the tumor cell surface. Notably, the d16HER2 variant significantly influences the initiation and aggressiveness of tumors, cancer stem cell properties, epithelial–mesenchymal transition (EMT), and the susceptibility of HER2-positive BC cells to trastuzumab compared with its wtHER2 counterpart, thus constituting a novel and potentially clinically useful biomarker. The aims of this review are to summarize the existing evidence regarding the pathobiological functions of the d16HER2 variant and discuss its current and future value with regard to risk assessment and treatment choices in HER2-positive disease. Full article

(This article belongs to the Special Issue Epidermal Growth Factor Receptor Signaling in Cancer)

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20 pages, 4888 KiB

Open AccessArticle

Butoxy Mansonone G Inhibits STAT3 and Akt Signaling Pathways in Non-Small Cell Lung Cancers: Combined Experimental and Theoretical Investigations

by Panupong Mahalapbutr¹, Piyanuch Wonganan^2,*, Warinthorn Chavasiri³

and Thanyada Rungrotmongkol^1,4,*

¹ Structural and Computational Biology Research Unit, Department of Biochemistry, Faculty of Science, Chulalongkorn University, Pathumwan, Bangkok 10330, Thailand

² Department of Pharmacology, Faculty of Medicine, Chulalongkorn University, Pathumwan, Bangkok 10330, Thailand

³ Center of Excellence in Natural Products Chemistry, Department of Chemistry, Faculty of Science, Chulalongkorn University, Pathumwan, Bangkok 10330, Thailand

⁴ Ph.D. Program in Bioinformatics and Computational Biology, Faculty of Science, Chulalongkorn University, Pathumwan, Bangkok 10330, Thailand

Cancers 2019, 11(4), 437; https://doi.org/10.3390/cancers11040437 - 28 Mar 2019

Cited by 25 | Viewed by 6186

Abstract

Epidermal growth factor receptor (EGFR) is the key molecular target for non-small cell lung cancer (NSCLC) due to its major contribution to complex signaling cascades modulating the survival of cancer cells. Targeting EGFR-mediated signaling pathways has been proved as a potential strategy for [...] Read more.

Epidermal growth factor receptor (EGFR) is the key molecular target for non-small cell lung cancer (NSCLC) due to its major contribution to complex signaling cascades modulating the survival of cancer cells. Targeting EGFR-mediated signaling pathways has been proved as a potential strategy for NSCLC treatment. In the present study, mansonone G (MG), a naturally occurring quinone-containing compound, and its semi-synthetic ether derivatives were subjected to investigate the anticancer effects on human NSCLC cell lines expressing wild-type EGFR (A549) and mutant EGFR (H1975). In vitro cytotoxicity screening results demonstrated that butoxy MG (MG3) exhibits the potent cytotoxic effect on both A549 (IC₅₀ of 8.54 μM) and H1975 (IC₅₀ of 4.21 μM) NSCLC cell lines with low toxicity against PCS201-010 normal fibroblast cells (IC₅₀ of 21.16 μM). Western blotting and flow cytometric analyses revealed that MG3 induces a caspase-dependent apoptosis mechanism through: (i) inhibition of p-STAT3 and p-Akt without affecting upstream p-EGFR and (ii) activation of p-Erk. The 500-ns molecular dynamics simulations and the molecular mechanics combined with generalized Born surface area (MM/GBSA)-based binding free energy calculations suggested that MG3 could possibly interact with STAT3 SH2 domain and ATP-binding pocket of Akt. According to principal component analysis, the binding of MG3 toward STAT3 and Akt dramatically altered the conformation of proteins, especially the residues in the active site, stabilizing MG3 mainly through van der Waals interactions. Full article

(This article belongs to the Special Issue Epidermal Growth Factor Receptor Signaling in Cancer)

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14 pages, 1230 KiB

Open AccessEditor’s ChoiceReview

Newer-Generation EGFR Inhibitors in Lung Cancer: How Are They Best Used?

by Tri Le¹ and David E. Gerber^1,2,3,*

¹ Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390-8852, USA

² Department of Clinical Sciences, University of Texas Southwestern Medical Center, Dallas, TX 75390-8852, USA

³ Division of Hematology-Oncology, Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX 75390-8852, USA

Cancers 2019, 11(3), 366; https://doi.org/10.3390/cancers11030366 - 15 Mar 2019

Cited by 63 | Viewed by 8968

Abstract

The FLAURA trial established osimertinib, a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), as a viable first-line therapy in non-small cell lung cancer (NSCLC) with sensitizing EGFR mutations, namely exon 19 deletion and L858R. In this phase 3 randomized, controlled, [...] Read more.

The FLAURA trial established osimertinib, a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), as a viable first-line therapy in non-small cell lung cancer (NSCLC) with sensitizing EGFR mutations, namely exon 19 deletion and L858R. In this phase 3 randomized, controlled, double-blind trial of treatment-naïve patients with EGFR mutant NSCLC, osimertinib was compared to standard-of-care EGFR TKIs (i.e., erlotinib or gefinitib) in the first-line setting. Osimertinib demonstrated improvement in median progression-free survival (18.9 months vs. 10.2 months; hazard ratio 0.46; 95% CI, 0.37 to 0.57; p < 0.001) and a more favorable toxicity profile due to its lower affinity for wild-type EGFR. Furthermore, similar to later-generation anaplastic lymphoma kinase (ALK) inhibitors, osimertinib has improved efficacy against brain metastases. Despite this impressive effect, the optimal sequencing of osimertinib, whether in the first line or as subsequent therapy after the failure of earlier-generation EGFR TKIs, is not clear. Because up-front use of later-generation TKIs may result in the inability to use earlier-generation TKIs, this treatment paradigm must be evaluated carefully. For EGFR mutant NSCLC, considerations include the incidence of T790M resistance mutations, quality of life, whether there is a potential role for earlier-generation TKIs after osimertinib failure, and overall survival. This review explores these issues for EGFR inhibitors and other molecularly targeted therapies. Full article

(This article belongs to the Special Issue Epidermal Growth Factor Receptor Signaling in Cancer)

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11 pages, 1907 KiB

Open AccessArticle

Nicotine Induces Resistance to Erlotinib Therapy in Non-Small-Cell Lung Cancer Cells Treated with Serum from Human Patients

by Tatsuya Imabayashi¹, Junji Uchino^1,*

, Hisayuki Osoreda², Keiko Tanimura¹, Yusuke Chihara¹, Nobuyo Tamiya¹, Yoshiko Kaneko¹, Tadaaki Yamada¹

and Koichi Takayama¹

¹ Department of Pulmonary Medicine, Kyoto Prefectural University of Medicine Graduate School of Medical Science, Kyoto 602-0841, Japan

² Department of Internal Medicine, Self Defense Forces Fukuoka Hospital, Fukuoka 816-0826, Japan

Cancers 2019, 11(3), 282; https://doi.org/10.3390/cancers11030282 - 27 Feb 2019

Cited by 10 | Viewed by 4094

Abstract

Previously, we reported that nicotine reduces erlotinib sensitivity in a xenograft model of PC9, an epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI)-sensitive non-small-cell lung cancer cell line. The present study examined whether smoking induces erlotinib resistance in vitro. We assessed resistance to EGFR-TKIs [...] Read more.

Previously, we reported that nicotine reduces erlotinib sensitivity in a xenograft model of PC9, an epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI)-sensitive non-small-cell lung cancer cell line. The present study examined whether smoking induces erlotinib resistance in vitro. We assessed resistance to EGFR-TKIs by treating cancer cell lines with erlotinib, afatinib, or osimertinib, and serum collected from smokers within 30 min of smoking and that from a non-smoker as a control. We also assessed erlotinib resistance by treating PC9 cells exposed to serum from a smoker or a non-smoker, or serum from an erlotinib user. Treatment of the cancer cell lines with serum from smokers induced significant erlotinib resistance, compared with the control (p < 0.05). Furthermore, serum samples with a high concentration of cotinine (a nicotine exposure indicator) demonstrated stronger erlotinib resistance than those with low concentrations. Similar to the observations with erlotinib treatment of cell lines, the analysis of serum from erlotinib users revealed that smokers demonstrated significantly reduced sensitivity to erlotinib (p < 0.001). In conclusion, our present results support the hypothesis that smoking contributes to resistance to erlotinib therapy in non-small-cell lung cancer. Full article

(This article belongs to the Special Issue Epidermal Growth Factor Receptor Signaling in Cancer)

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20 pages, 3445 KiB

Open AccessArticle

Overcoming Intrinsic and Acquired Cetuximab Resistance in RAS Wild-Type Colorectal Cancer: An In Vitro Study on the Expression of HER Receptors and the Potential of Afatinib

by Ines De Pauw^1,*

, Filip Lardon¹

, Jolien Van den Bossche¹

, Hasan Baysal¹, Patrick Pauwels^1,2, Marc Peeters^1,3, Jan Baptist Vermorken^1,3 and An Wouters¹

¹ Center for Oncological Research (CORE), University of Antwerp, 2610 Wilrijk, Belgium

² Department of Pathology, Antwerp University Hospital, 2650 Edegem, Belgium

³ Department of Oncology, Antwerp University Hospital, 2650 Edegem, Belgium

Cancers 2019, 11(1), 98; https://doi.org/10.3390/cancers11010098 - 15 Jan 2019

Cited by 13 | Viewed by 7888

Abstract

The epidermal growth factor receptor (EGFR) is an important therapeutic target in colorectal cancer (CRC). After the initial promising results of EGFR-targeted therapies such as cetuximab, therapeutic resistance poses a challenging problem and limits the success of effective anti-EGFR cancer therapies in the [...] Read more.

The epidermal growth factor receptor (EGFR) is an important therapeutic target in colorectal cancer (CRC). After the initial promising results of EGFR-targeted therapies such as cetuximab, therapeutic resistance poses a challenging problem and limits the success of effective anti-EGFR cancer therapies in the clinic. In order to overcome resistance to these EGFR-targeted therapies, new treatment options are necessary. The objective of this study was to investigate the expression of human epidermal growth factor (HER) receptors and the efficacy of afatinib, a second-generation irreversible EGFR-tyrosine kinase inhibitor, in RAS wild-type CRC cell lines with different cetuximab sensitivities. CRC cell lines with different sensitivities to cetuximab showed rather low EGFR expression but high HER2 and HER3 expression. These results were in line with the The Cancer Genome Atlas (TCGA) data from CRC patients, where higher mRNA levels of HER2 and HER3 were also detected compared to EGFR. Therefore, the targets of afatinib were indeed expressed on the CRC cell lines used in this study and in CRC patients. Furthermore, cetuximab resistance had no significant influence on the expression levels of HER receptors in CRC cell lines (p ≥ 0.652). This study also demonstrated that afatinib was able to induce a concentration-dependent cytotoxic effect in RAS wild-type CRC cell lines with different cetuximab sensitivities. Neither cetuximab resistance (p = 0.233) nor hypoxia (p = 0.157) significantly influenced afatinib’s cytotoxic effect. In conclusion, our preclinical data support the hypothesis that treatment with afatinib might be a promising novel therapeutic strategy for CRC patients experiencing intrinsic and acquired cetuximab resistance. Full article

(This article belongs to the Special Issue Epidermal Growth Factor Receptor Signaling in Cancer)

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10 pages, 505 KiB

Open AccessArticle

Risk Factors for Severe Diarrhea with an Afatinib Treatment of Non-Small Cell Lung Cancer: A Pooled Analysis of Clinical Trials

by Ashley M. Hopkins¹, Anh-Minh Nguyen¹, Christos S. Karapetis^1,2, Andrew Rowland¹ and Michael J. Sorich^1,*

¹ College of Medicine and Public Health, Flinders University, Adelaide 5042, Australia

² Department of Medical Oncology, Flinders Medical Centre, Adelaide 5042, Australia

Cancers 2018, 10(10), 384; https://doi.org/10.3390/cancers10100384 - 15 Oct 2018

Cited by 13 | Viewed by 4456

Abstract

Afatinib is an effective therapy for metastatic non-small cell lung cancer (NSCLC) but it is associated with a relatively high incidence of severe diarrhea. The association between pre-treatment candidate predictors (age, sex, race, performance status, renal function, hemoglobin, and measures of body mass) [...] Read more.

Afatinib is an effective therapy for metastatic non-small cell lung cancer (NSCLC) but it is associated with a relatively high incidence of severe diarrhea. The association between pre-treatment candidate predictors (age, sex, race, performance status, renal function, hemoglobin, and measures of body mass) and severe (grade ≥ 3) diarrhea was evaluated using logistic regression with pooled individual participant data from seven clinical studies. A risk score was developed based on the count of major risk factors. Overall, 184 of 1151 participants (16%) experienced severe diarrhea with use of afatinib. Body weight, body mass index, and body surface area all exhibited a prominent non-linear association where risk increased markedly at the lower range (p < 0.005). Low weight (<45 kg), female sex, and older age (≥60 years) were identified as major independent risk factors (p < 0.01). Each risk factor was associated with a two-fold increase in the odds of severe diarrhea, and this was consistent between individuals commenced on 40 mg or 50 mg afatinib. A simple risk score based on the count of these risk factors identifies individuals at lowest and highest risk (C-statistic of 0.65). Risk of severe diarrhea for individuals commenced on 40 mg afatinib ranged from 6% for individuals with no risk factors to 33% for individuals with all three risk factors. Full article

(This article belongs to the Special Issue Epidermal Growth Factor Receptor Signaling in Cancer)

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Open AccessArticle

A Novel Role for the Interleukin-1 Receptor Axis in Resistance to Anti-EGFR Therapy

by Valerio Gelfo^1,2,†

, Martina Mazzeschi^1,†, Giada Grilli¹, Moshit Lindzen³, Spartaco Santi^4,5

, Gabriele D’Uva⁶

, Balázs Győrffy^7,8, Andrea Ardizzoni¹, Yosef Yarden³ and Mattia Lauriola^1,2,*

¹ Department of Experimental, Diagnostic and Specialty Medicine (DIMES), University of Bologna, 40138 Bologna, Italy

² Centre for Applied Biomedical Research (CRBA), Bologna University Hospital Authority St. Orsola-Malpighi Polyclinic, 40138 Bologna, Italy

³ Department of Biological Regulation, Weizmann Institute of Science, 7610001 Rehovot, Israel

⁴ Institute of Molecular Genetics, National Research Council of Italy, 40136 Bologna, Italy

⁵ IRCCS-Istitute Orthopaedic Rizzoli, 40136 Bologna, Italy

⁶ Scientific and Technology Pole, IRCCS MultiMedica, 20138 Milan, Italy

⁷ MTA TTK Lendület Cancer Biomarker Research Group, Institute of Enzymology, Magyar Tudósok körútja 2, 1117 Budapest, Hungary

⁸ Semmelweis University 2nd Dept. of Pediatrics, Tűzoltó utca 7–9, 1094 Budapest, Hungary

^† These authors contributed equally to this work.

Cancers 2018, 10(10), 355; https://doi.org/10.3390/cancers10100355 - 26 Sep 2018

Cited by 27 | Viewed by 5785

Abstract

Cetuximab (CTX) is a monoclonal antibody targeting the epidermal growth factor receptor (EGFR), commonly used to treat patients with metastatic colorectal cancer (mCRC). Unfortunately, objective remissions occur only in a minority of patients and are of short duration, with a population of cells [...] Read more.

Cetuximab (CTX) is a monoclonal antibody targeting the epidermal growth factor receptor (EGFR), commonly used to treat patients with metastatic colorectal cancer (mCRC). Unfortunately, objective remissions occur only in a minority of patients and are of short duration, with a population of cells surviving the treatment and eventually enabling CTX resistance. Our previous study on CRC xenopatients associated poor response to CTX with increased abundance of a set of pro-inflammatory cytokines, including the interleukins IL-1A, IL-1B and IL-8. Stemming from these observations, our current work aimed to assess the role of IL-1 pathway activity in CTX resistance. We employed a recombinant decoy TRAP IL-1, a soluble protein combining the human immunoglobulin Fc portion linked to the extracellular region of the IL-1-receptor (IL-1R1), able to sequester IL-1 directly from the medium. We generated stable clones expressing and secreting a functional TRAP IL-1 into the culture medium. Our results show that IL-1R1 inhibition leads to a decreased cell proliferation and a dampened MAPK and AKT axes. Moreover, CRC patients not responding to CTX blockage displayed higher levels of IL-1R1 than responsive subjects, and abundant IL-1R1 is predictive of survival in patient datasets specifically for the consensus molecular subtype 1 (CMS1). We conclude that IL-1R1 abundance may represent a therapeutic marker for patients who become refractory to monoclonal antibody therapy, while inhibition of IL-1R1 by TRAP IL-1 may offer a novel therapeutic strategy. Full article

(This article belongs to the Special Issue Epidermal Growth Factor Receptor Signaling in Cancer)

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