Small Cell Lung Carcinoma: Current Diagnosis, Biomarkers, and Treatment Options with Future Perspectives
Abstract
:1. Introduction
2. Pathology of SCLC
3. Genomic Features of SCLC
Gene | Aliases | Gene Location on Human Chromosome and Number of Amino Acids | Gene Alteration in SCLC | Known Function and Features | Frequency of Mutation in SCLC (% in Various Cohorts) | Refs. |
---|---|---|---|---|---|---|
TP53 | Tumor protein 53; p53; Phosphoprotein P53; Antigen NY-CO-13; Transformation-Related Protein 53; BCC7, LFS1, TRP53, tumor protein BMFS5 | Chromosome 17 at position 17p13.1.; 375 amino acids | Inactivating mutation; deletion | Nuclear phosphoprotein involved in the regulation of cell proliferation; tumor suppressor; transcription regulation | 77–89 | Chang et al. [31] Rudin et al. [23] |
RB1 | RB1, pRb, RB, retinoblastoma 1, OSRC, PPP1R130, p105-Rb, pp110, Retinoblastoma protein, RB transcriptional corepressor 1, p110-RB1 | Chromosome 13 at position 13q14.1-q14.2.; 928 amino acids | Inactivating mutation; deletion; loss or inactivation of both copies of the gene | Tumor suppressor protein that is dysfunctional in several major cancers. Prevents excessive cell growth by inhibiting cell cycle progression -key regulator of the G1/S transition of the cell cycle | 50–90 | George et al. [21] Febres-Aldana et al. [32] |
KMT2D | KMT2D, ALR, KABUK1, MLL2, MLL4, lysine methyltransferase 2D, histone-lysine methyltransferase 2D, TNRC21, AAD10, KMS, CAGL114 | Chromosome 12 at position 12q13.12.; 5316 amino acids | Inactivating mutation; deletion; gene fusion; truncating nonsense/frameshift/splice site mutations | Key regulator of transcriptional enhancer function; major enhancer regulator in mammalian cells, including regulation of development, differentiation, metabolism, and tumor suppression. | 5–13 | Wu et al. [33] Simbolo et al. [34] Augert et al. [35] |
CREBBP | AW558298, CBP, CBP/p300, KAT3A, p300/CBP, RSTS, CREB binding protein, RSTS1, MKHK1 | Chromosome 16 at position 16p13.3. 2414 amino acids. | Inactivating mutation, deletion | Crucial role in transcriptional regulation and chromatin remodeling. Interacts with various transcription factors and coactivators, influencing the expression of target genes involved in cell growth, differentiation, and development. | 4–10 | Carazo et al. [36] Jia et al. [37] |
PTEN | PTEN, 10q23del, BZS, CWS1, DEC, GLM2, MHAM, MMAC1, PTEN1, TEP1, phosphatase and tensin homolog, Phosphatase and tensin homolog, PTENbeta | Chromosome 10 at position 10q23.3. 403 amino acids | inactivating mutations, deletions, or loss of expression | Tumor suppressor involved in the regulation of the PI3K/AKT/mTOR pathway, which plays a critical role in cell survival and proliferation. PTEN’s protein phosphatase activity may be involved in the regulation of the Cell cycle, preventing cells from growing and dividing too rapidly. | 3–10 | Sivakumar et al. [38] Zhang et al. [39] |
FAT1 | CDHF7, CDHR8, FAT, ME5, hFat1, FAT atypical cadherin 1 | Chromosome 4 at position 4q35.2. 4410 amino acids | Inactivation mutation; deletion | Cell-cell adhesion, migration and communication, regulation of tissue growth, cell polarity, and migration; tumor suppressor gene | 2–10 | JiaXin et al. [40] Pop-Bica et al. [41] |
PIK3CA | PIK3CA, CLOVE, CWS5, MCAP, MCM, MCMTC, PI3K, p110-alpha, PI3K-alpha, phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha, CLAPO, CCM4 | Chromosome 3 at position 3q26.3.; 1068 amino acids | Activating mutation; mutations in specific regions | The PIK3CA gene for synthesis of the catalytic subunit alpha of the enzyme phosphatidylinositol 3-kinase, having crucial role in cell growth, proliferation, and survival | 1–7 | Hung et al. [42] Pop-Bica et al. [41] |
NOTCH1 | NOTCH1, Notch1, 9930111A19Rik, Mis6, N1, Tan1, lin-12, AOS5, AOVD1, hN1 | Chromosome 9 at position 9q34.3. 2527 amino acids | Inactivating mutation | Tumor suppressor; involved in cell signalling processes | 1–6 | Li et al. [43] Roper et al. [44] Herbreteau et al. [45] |
NF1 | NFNS, VRNF, WSS, neurofibromin 1 | Chromosome 17 at position 17q11.2. 2818 amino acids | Inactivating mutation, deletion | Tumor suppressor. Neurofibromin 1 plays a role in regulating cell growth and proliferation by negatively regulating the activity of Ras, associated with uncontrolled cell growth. | 3–4 | Ross et al. [46] Shimizu et al. [47] |
APC | BTPS2, DP2, DP2.5, DP3, GS, PPP1R46, adenomatous polyposis coli, WNT signaling pathway regulator | Chromosome 5 at position 5q22.2. 2843 amino acids | Inactivating mutation, deletion | Crucial role in regulating the Wnt signaling pathway and controlling cell proliferation, growth, differentiation, and migration. | 3–4 | Jin et al. [48] Grote et al. [49] |
EGFR | ERBB, ERBB1, HER1, NISBD2, PIG61, mENA, epidermal growth factor receptor, erbB-1, ERRP | Chromosome 7 at position 7p12.1. 1210 amino acids | Activating mutation | Oncogene; a receptor tyrosine kinase that plays a critical role in cell growth, proliferation, and survival; involved in RAS signaling pathway. | 3–4 | Ding et al. [50] Hao et al. [51] |
KRAS | C-K-RAS, CFC2, K-RAS2A, K-RAS2B, K-RAS4A, K-RAS4B, KI-RAS, KRAS1, KRAS2, NS, NS3, RALD, RASK2, K-ras, KRAS proto-oncogene, GTPase, c-Ki-ras2, OES, c-Ki-ras, K-Ras 2, K-Ras, Kirsten Rat Sarcoma virus | Chromosome 12 at position 12p12.1. 189 amino acids | Activating mutation | A GTPase involved in cell signalingpathways that regulate cell growth and proliferation (RAS/MAPK). KRAS mutations can lead to the constitutive activation of the KRAS protein, resulting in dysregulated cell signaling and increased cell proliferation. | 1–3 | Otegui et al. [52] Li et al. [53] |
NOTCH3 | CADASIL, CASIL, IMF2, LMNS, CADASIL1, notch 3, notch receptor 3 | Chromosome 19 at position 19p13.2. 2345 amino acids | Inactivating mutation, deletion | Involved in cell signaling pathways. Notch signaling plays a critical role in cellular processes, such as cell fate determination, differentiation, and development. | <3 | Herbreteau et al. [45] Du et al. [54] |
ARID1A | B120, BAF250, BAF250a, BM029, C1orf4, ELD, MRD14, OSA1, P270, SMARCF1, hELD, hOSA1, CSS2, AT-rich interaction domain 1A | Chromosome 1 at position 1p36.11. 2254 amino acids | Inactivating mutation, deletion | Tumor suppressor gene; plays a crucial role in regulating chromatin remodeling and gene expression; involved in various cellular processes, including DNA repair, cell cycle regulation, and differentiation. | <3 | Du et al. [54] Devarakonda et al. [55] |
PTPRD | HPTP, HPTPD, HPTPDELTA, PTPD, RPTPDELTA, protein tyrosine phosphatase, receptor type D, protein tyrosine phosphatase receptor type D, R-PTP-delta | Chromosome 9 at position 9p23.3. 1840 amino acids | Inactivating mutation, deletion | Protein tyrosine phosphatase receptor that plays a role in regulating cell signaling pathways, including those involved in cell growth, differentiation, and migration. | <3 | Sato et al. [56] |
ATRX | ATR2, JMS, MRXHF1, RAD54, RAD54L, SFM1, SHS, XH2, XNP, ZNF-HX, MRX52, alpha thalassemia/mental retardation syndrome X-linked, chromatin remodeler, ATRX chromatin remodeler | X chromosome at position Xq21.1. | Inactivating mutation, deletion | Tumor suppressor; plays a critical role in chromatin remodeling and the regulation of gene expression. ATRX is involved in maintaining the stability and structure of telomeres and in cell signaling | <2 | Du et al. [54] |
4. Biomarkers in SCLC
Biomarker | Type | Potential Application | References |
---|---|---|---|
Delta-like ligand 3 DLL3 | Tumor-specific marker | Biomarker for SCLC prognosis | Chen et al. [58] |
Circulating tumor cells (CTC) | Liquid biopsy biomarker | Prognostic biomarker for therapy evaluation of therapy efficacy | Roumeliotou et al. [59] |
Circulating tumor DNA (ctDNA) | Liquid biopsy biomarker | Biomarker for treatment efficacy and relapse detection | Almodovar et al. [60] |
Exosomes | Extracellular vesicles | Non-invasive biomarkers for prognosis | Zhang et al. [61] |
MYC proto-oncogene/bHLH transcription factor (MYC) | Genetic alteration | Potential biomarker for targeted therapy | Taniguchi et al. [62] |
Programmed death-ligand 1 (PD-L1) | Immune checkpoint protein | Potential biomarker for immunotherapy response | Taniguchi et al. [62] |
Tumor mutational burden (TMB) | Mutation load of a tumor | Potential biomarker for immunotherapy response | Taniguchi et al. [62] and Li et al. [65] |
Microsatellite instability (MSI-H) | Genetic marker of Microsatellite Instability | Potential biomarker for immunotherapy response | Taniguchi et al. [62] and Chang et al. [66] |
Schlafen 11 (SLFN11) | Liquid biopsy biomarker | Potential biomarker for the response on DNA damaging chemotherapy and PARP inhibition | Taniguchi et al. [62] and Zhang et al. [63] |
4.1. Biomarkers of Response to Immune Checkpoint Inhibitors in SCLC
4.1.1. PD-L1 Expression in SCLC
4.1.2. Tumor Mutational Burden (TMB)
4.1.3. Microsatellite Instability (MSI-H) in SCLC
4.1.4. Delta-Like Ligand 3 (DLL3)
5. SCLC Treatment and Approaches to SCLC Therapy
5.1. Limited Stage
5.2. Extensive Stage
6. New Drugs in the Second Line or Beyond
7. Conclusions
Author Contributions
Funding
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Stage of the Disease | Treatment Options |
---|---|
Limited | Lobectomy with mediastinal dissection for stage I or II disease after extensive staging |
Adjuvant chemotherapy with cisplatin and etoposide for negative mediastinal lymph nodes and margins | |
Chemoradiotherapy for positive mediastinal lymph nodes or R1–R2 margins | |
Prophylactic cranial radiotherapy (PCI) in case of response to therapy | |
The preferred regimen for chemoradiotherapy: Cisplatin 75 mg/m2 day one and etoposide 100 to 120 mg/m2 day 1–3 | |
External radiotherapy in a total dose of 45 Gy twice daily (BID) | |
A total radiotherapy dose of 60 Gy once daily is not inferior to 45 Gy BID (CONVERT study) | |
Extensive-stage: First-line | Chemoimmunotherapy with atezolizumab or durvalumab in combination with platinum-based chemotherapy |
Carboplatin or cisplatin in combination with etoposide | |
Consolidation radiotherapy of the lung and prophylactic cranial irradiation (PCI) or MRI brain surveillance if there is a response to chemotherapy | |
Extensive-stage: Second-line | Platinum reinitiation in platinum-sensitive disease |
Chemotherapy (topotecan, CAV protocol, irinotecan, gemcitabine, temozolomide, docetaxel) | |
Lurbinectedin (for platinum-sensitive or resistant disease relapse) | |
Extensive-stage: Second line or beyond | New emerging therapeutic strategies under investigation (Aurora kinase A inhibitor, poly ADP ribose polymerase (PARP) inhibitor, ataxia telangiectasia, and Rad3 related (ATR) kinase inhibitor, Checkpoint kinase 1 (CHK1) inhibitor, Delta-like ligand 3 (DLL3) inhibitor, MYC inhibitor, Ganglioside fucosyl-GM1, an inhibitor of the bromodomain (BRD) and extra-terminal domain (BET) family of proteins |
Rovalpituzumab tesirine (not proven benefit in phase III randomized controlled trial) | |
Tarlatamab (TMG 757)—DLL3-targeted bispecific T-Cell engager | |
Olaparib (poly ADP ribose polymerase- PARP inhibitor) in combination with temozolomide | |
Aurora kinase inhibitors (positive signals in patients with c-MYC expression SCLC) | |
ATR inhibitor in combination with topotecan |
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Krpina, K.; Vranić, S.; Tomić, K.; Samaržija, M.; Batičić, L. Small Cell Lung Carcinoma: Current Diagnosis, Biomarkers, and Treatment Options with Future Perspectives. Biomedicines 2023, 11, 1982. https://doi.org/10.3390/biomedicines11071982
Krpina K, Vranić S, Tomić K, Samaržija M, Batičić L. Small Cell Lung Carcinoma: Current Diagnosis, Biomarkers, and Treatment Options with Future Perspectives. Biomedicines. 2023; 11(7):1982. https://doi.org/10.3390/biomedicines11071982
Chicago/Turabian StyleKrpina, Kristina, Semir Vranić, Krešimir Tomić, Miroslav Samaržija, and Lara Batičić. 2023. "Small Cell Lung Carcinoma: Current Diagnosis, Biomarkers, and Treatment Options with Future Perspectives" Biomedicines 11, no. 7: 1982. https://doi.org/10.3390/biomedicines11071982