☆ 4.7 Article

Genomic and pathological heterogeneity in clinically diagnosed small cell lung cancer in never/light smokers identifies therapeutically targetable alterations

MOLECULAR ONCOLOGY (2021)

Journal

MOLECULAR ONCOLOGY

Volume 15, Issue 1, Pages 27-42

Publisher

WILEY

DOI: 10.1002/1878-0261.12673

Keywords

combination therapy; lung cancers in never smokers; non‐ neuroendocrine SCLC; RAS mutation; small‐ cell lung cancer

Funding

American Cancer Society [CRP-17-111-01-CDD]
Mock Family Fund
Poduska Family Foundation Research Fund for Thoracic Oncology

Ask authors/readers for more resources

Protocol

Community support

Reagent

Community support

Automated Summary New
Abstract

SCLC is rare in never/former light smokers, with a majority of clinically diagnosed cases found to be nonpulmonary origin or mixed histology. Genomic profiling revealed diverse driver mutations and sensitivity to specific inhibitors, highlighting the importance of comprehensive pathologic review in refining diagnosis and identifying therapeutic options.

Small-cell lung cancer (SCLC) occurs infrequently in never/former light smokers. We sought to study this rare clinical subset through next-generation sequencing (NGS) and by characterizing a representative patient-derived model. We performed targeted NGS, as well as comprehensive pathological evaluation, in 11 never/former light smokers with clinically diagnosed SCLC. We established a patient-derived model from one such patient (DFCI168) harboring an NRAS(Q61K) mutation and characterized the sensitivity of this model to MEK and TORC1/2 inhibitors. Despite the clinical diagnosis of SCLC, the majority (8/11) of cases were either of nonpulmonary origin or of mixed histology and included atypical carcinoid (n = 1), mixed non-small-cell lung carcinoma and SCLC (n = 4), unspecified poorly differentiated carcinoma (n = 1), or small-cell carcinoma from different origins (n = 2). RB1 and TP53 mutations were found in four and five cases, respectively. Predicted driver mutations were detected in EGFR (n = 2), NRAS (n = 1), KRAS (n = 1), BRCA1 (n = 1), and ATM (n = 1), and one case harbored a TMPRSS2-ERG fusion. DFCI168 (NRAS(Q61K)) exhibited marked sensitivity to MEK inhibitors in vitro and in vivo. The combination of MEK and mTORC1/2 inhibitors synergized to prevent compensatory mTOR activation, resulting in prolonged growth inhibition in this model and in three other NRAS mutant lung cancer cell lines. SCLC in never/former light smokers is rare and is potentially a distinct disease entity comprised of oncogenic driver mutation-harboring carcinomas morphologically and/or clinically mimicking SCLC. Comprehensive pathologic review integrated with genomic profiling is critical in refining the diagnosis and in identifying potential therapeutic options.

Authors

I am an author on this paper

Click your name to claim this paper and add it to your profile.

Reviews

Primary Rating

4.7

Not enough ratings

Secondary Ratings

Novelty

Significance

Scientific rigor

Rate this paper

Small molecular inhibitors for KRAS-mutant cancers

Xuan Wu, Wenping Song, Cheng Cheng, Ziyang Liu, Xiang Li, Yu Cui, Yao Gao, Ding Li

Summary: Three isoforms of RAS gene, KRAS, NRAS, and HRAS, are the most mutated family of small GTPases in cancer. While targeted immunotherapies have improved the survival of patients with non-KRAS-mutant cancer, RAS-mutant cancers still have a poor prognosis due to their high aggressiveness. However, recent advances in the use of allele-specific covalent inhibitors have led to the development of effective pharmacological interventions against RAS-mutant cancer, such as Sotorasib (AMG510) for KRAS-G12C mutant NSCLC. This review summarizes the progress and promise of small-molecule inhibitors in clinical trials to improve the prognosis of tumors with RAS mutations.

FRONTIERS IN IMMUNOLOGY (2023)