Molecular profiles of small cell lung cancer subtypes: therapeutic implications

Small cell lung cancer (SCLC) accounts for approximately 15% of all lung cancer cases and features a strong predilection for early metastasis and extremely poor prognosis. Despite being highly sensitive to chemotherapy and/or radiotherapy initially, most SCLC patients develop therapeutic resistance within one year and die of distant metastases. Multiple studies have revealed the high heterogeneity and strong plasticity of SCLC associated with frequent metastases and early development of therapeutic resistance as well as poor clinical outcome. Importantly, different SCLC subtypes are associated with different therapeutic vulnerabilities, and the inflamed subtype tends to have the best response to immunotherapy, which highlights the importance of precision medicine in the clinic. Here, we review recent advances in SCLC heterogeneity and plasticity and their link to distant metastases and chemotherapy resistance. We hope that a better understanding of the molecular mechanisms underlying SCLC malignant progression will help to develop better intervention strategies for this deadly disease.

Understanding SCLC heterogeneity and plasticity in cancer metastasis and chemotherapy resistance

Purpose: The purpose of this study was to investigate the effect of MYC and TP53 comutations on the clinical efficacy of EGFR tyrosine kinase inhibitors (TKIs) in Chinese patients with advanced EGFR-positive nonsmall-cell lung cancer (NSCLC). Patients and methods: Tissue samples and information from 65 patients with advanced NSCLC in Northern Jiangsu People's Hospital were collected and analyzed by next-generation sequencing (NGS). Progression-free survival (PFS) and total survival (OS) were the main endpoints, and the objective response rate (ORR) and disease control rate (DCR) were the secondary endpoints. Result: Among 65 patients, 17 had TP53 and MYC wild-type mutations (WT/WT), 36 had TP53 mutant and MYC wild-type mutations (TP53/WT), and 12 had coexisting MYC/TP53 mutations (MYC/TP53). When 12 patients with MYC/TP53 comutation were compared with the other two groups (TP53/WT, WT/WT), mPFS and mOS are significantly lower than those in the other two groups (mPFS: 4.1 months vs 6.0 months, 12.3 months, HR: 0.769, 95% CI: 4.592-7.608, P  =  .047. mOS: 14.6 months vs 24.1 months, 31.5 months, HR: 3.170, 95% CI: 18.786-31.214, P < .001), and the ORR, DCR of patients with MYC/TP53 comutation was lower than that of the other two groups (ORR, 25% vs 44.4%, 70.6%, P  =  .045. DCR, 58.3% vs 72.2%, 82.4%, P  =  .365). Conclusion: Patients with MYC/TP53 comutations with EGFR-positive advanced NSCLC are more likely to develop drug resistance after early treatment with EGFR-TKIs and have a worse clinical outcome.

Evaluate the Prognosis of MYC/TP53 Comutation in Chinese Patients with EGFR-Positive Advanced NSCLC Using Next-Generation Sequencing: A Retrospective Study

NOTCH Your Usual Suspect: MYC Charged with Controlling Neuroendocrine Cell-Fate in Small Cell Lung Cancer.

Introduction The classification of small cell lung cancer (SCLC) into distinct molecular subtypes defined by ASCL1, NEUROD1, POU2F3 or YAP1 expression, paves the way for the development of targeted therapeutics. However, the existence of a distinct YAP1-expressing SCLC subtype remains controversial. Here we have undertaken a detailed molecular and histological characterisation of YAP1 expressing SCLC-Y to understand the biology of this proposed subtype. Methods The mutational landscape of human SCLC cell lines was interrogated to identify pathogenic genomic alterations unique to SCLC-Y. Xenograft tumours generated from cell lines representing the molecular subtypes of SCLC (SCLC-A, -N, -P and -Y) were evaluated by a panel of pathologists. Diagnoses were validated by transcriptomic analysis of primary tumour and human cell line datasets. Results Unexpectedly, pathogenic mutations in SMARCA4 were identified in six of eight SCLC-Y cell lines and correlated with reduced SMARCA4 mRNA and protein expression. Pathologist evaluations revealed that SMARCA4-deficient SCLC-Y tumours exhibited features consistent with thoracic SMARCA4-deficient undifferentiated tumours (SMARCA4-UT). Similarly, the transcriptional profile SMARCA4-mutant SCLC-Y lines more closely resembled primary SMARCA4-UT, or SMARCA4-deficient non-small cell carcinoma, than SCLC. Combining clinical, pathological, transcriptomic, and genetic data we found little evidence to support a diagnosis of SCLC for any of the YAP1-expressing cell lines originally used to define the SCLC-Y subtype. Conclusions SCLC-Y cell lines harbour inactivating SMARCA4 mutations and exhibit characteristics consistent with SMARCA4-deficient malignancies rather than SCLC. Our findings suggest that, unlike ASCL1, NEUROD1 and POU2F3, YAP1 is not a subtype defining transcription factor in SCLC.

/pdf/brief-report-reclassifying-sclc-y-as-smarca4-deficient-29zqp9g6.pdf

Brief report: Reclassifying SCLC-Y as SMARCA4 deficient malignancies - resolving the controversy

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NOTCH Your Usual Suspect: MYC Charged with Controlling Neuroendocrine Cell-Fate in Small Cell Lung Cancer.

Brief report: Reclassifying SCLC-Y as SMARCA4 deficient malignancies - resolving the controversy