Key Signatures, Potential Vulnerabilities of SCLC Identified

New research into small-cell lung cancer (SCLC) is offering insights into the complexity of the cancer type and offering a potential new therapeutic avenue.

The report was published in Signal Transduction and Targeted Therapy.¹ It suggests that focal adhesion kinase (FAK) inhibition should be considered as a possible therapeutic target.

While SCLC represents a minority of lung cancer cases, it carries with it a particularly poor prognosis, the authors explained. They noted that the 5-year overall survival for the cancer type is less than 7%.² Yet, relatively little is known about SCLC compared to other cancer types because surgical treatment is rare among patients with SCLC, and thus there are relatively few specimens available for in-depth examination. That has led to significant knowledge gaps.¹

“In SCLC, loss-of-function mutations have been detected in tumor suppressors, including TP53 and RB1, but high-frequency gain-of-function mutations in oncogenes have rarely been identified,” they wrote.

The authors added that increased intratumoral heterogeneity (ITH) and an immunosuppressive tumor microenvironment have been identified across subtypes of SCLC. However, they said there remains a need for multiomics studies to identify more high-frequency gain-of-function alterations in oncogenes and molecular subtypes in order to better optimize treatment.

The investigators noted that SCLC is closely linked to tobacco smoke and environmental carcinogens. They said carcinogens have been linked with an increased risk of alternative splicing, in which splice sites “are differentially utilized to produce different mRNA isoforms, contributing to the abnormal activation of oncogenic pathways.”

Alternative splicing events (ASEs) have been detected in several genes in cases of SCLC, the authors noted, but the profiles and roles of ASEs in the disease’s onset have not been thoroughly studied. In addition, they said the specific carcinogenic compounds responsible for SCLC have also yet to be discovered.

In the new study, researchers used single-cell RNA sequencing, bulk RNA sequencing, ASE assessment, chemokine analysis, 16S ribosomal RNA gene sequencing, and whole-exome sequencing on 314 samples from patients with SCLC. The samples came from 10 hospitals across China, three-quarters of the patients were male, and 150 were under the age of 60. Two-thirds of the cohort were smokers, 125 had stage IA-IIB disease, and 154 had stage IIIA-IV disease.

The investigators found that the ASCL1+/MKI67+ and ASCL1+/CRIP2+ clusters made up the large majority (74.38%) of the 190,313 SCLC cancer cells from 39 patients analyzed and that the ASCL1+SOX1+ stem-like cell cluster was found across SCLC subtypes.

They found that the major histocompatibility complex (MHC) class I molecules were expressed at varying levels—low in six cancer cell clusters and high in 5 cancer cell clusters—and that those levels were inversely associated with KI67 expression.

“Hence, the heterogeneity of MHC expression in SCLC cell clusters and the role of MKI67 in the regulation of MHC-I and MHC-II warrant further investigation,” they wrote.

The research also showed that abnormal mRNA splicing is common in SCLC, with FAK splicing variants found in 77.3% of patients.

“FAK variants exhibited elevated kinase activity, were associated with the worst prognosis, and were sensitive to FAK inhibitors in patient-derived organoids and xenograft models,” they explained.

The authors said FAK splicing variants appear to be high-frequency gain-of-function alterations, and therefore ought to be seen as potential therapeutic targets.

The authors also found 11 additional high-frequency mutations beyond TP53 and RB1, and found that smoking status and tumor stage were not associated with microbiota variance.

References

1. Wang GZ, Wang Z, Bai SH, et al. Characterization of the extrinsic and intrinsic signatures and therapeutic vulnerability of small cell lung cancers. Signal Transduct Target Ther. 2025;10(1):290. doi:10.1038/s41392-025-02378-6

2. Megyesfalvi Z, Gay CM, Popper H, et al. Clinical insights into small cell lung cancer: Tumor heterogeneity, diagnosis, therapy, and future directions. CA Cancer J Clin. 2023;73(6):620-652. doi:10.3322/caac.21785