Genetic classification of SCLC

There are ongoing efforts to develop a precision medicine approach in small cell lung cancer (SCLC) where patients can be stratified based on their tumour molecular profile and treated with optimal targeted therapies. In this regard, Umemura et-al attempted to classify SCLC into clinically-relevant subtypes based on genetic profiling of a large sample size of tumour tissues via next-generation sequencing testing (J Thoracic Oncol 2025;doi: 10.1016/j.jtho.2024.10.004). According to their findings, patients with SCLC can be classified into five molecular subtypes: NSCLC (genetic alterations associated with non-small cell lung cancer (NSCLC)), PI3K (phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathway mutations), HME (mutations in the histone-modifying enzymes), MYC (MYC family amplifications), and Hotspot (targetable hotspot mutations common in tumours). These subtypes were associated with distinct clinical data, with the NSCLC and MYC subtypes exhibiting poorer prognosis in response to chemotherapy while the HME subtype patients displayed improved outcomes under treatment with chemo-immunotherapy. Umemura et-al also conducted a phase II clinical trial of gedatolisib (a potent inhibitor of all class I PI3K isoforms, mTORC1, and mTORC2) for SCLC which exhibited therapeutic efficacy only in SCLC patients categorised in the PI3K subgroup.

Overall, the findings of this study provide important molecular insights into the heterogeneity of the biology of SCLCs, represent a step forward towards reaching precision medicine in SCLC, and will function as a springboard for future investigations in the field.

Targeting SWI/SNF complex in SCLC sybtype

In this study, Duplaquet et-al focused on the biology of the POU class 2 homeobox 3 (POU2F3) transcription factor SCLC subtype, which represents approximately 12% of all SCLC cases, investigating the molecular mechanisms that govern its oncogenic transcriptional programme and probing for actionable therapeutic targets (Cancer Cell 2024; doi: 10.1016/j.ccell.2024.06.012). Genomic screening in POU2F3-positive SCLC cells identified members of the mammalian SWItch/Sucrose Non-Fermentable (mSWI/SNF) complex (a group of proteins that associate to remodel the way DNA is packaged), including bromodomain-containing protein 9 (BRD9) and SWI/SNF-related BAF chromatin remodelling complex subunit ATPase 4 (SMARCA4), as key regulators of POU2F3 gene expression and POU2F3-driven proliferation.

Indeed, BRD9 degradation and mSWI/SNF ATPase activity inhibition with selective pharmacological agents led to reduced POU2F3 protein levels as well as attenuated proliferation of POU2F3-positive SCLC cells. As BRD9 degraders did not affect all POU2F3-expressing SCLC cell lines, Duplaquet et-al examined the molecular underpinnings behind this lack of drug response and revealed that POU2F3-positive SCLC cells can be classified into two separate groups according to their neuroendocrine status (expression of genes fostering neuroendocrine differentiation) and sensitivity to BRD9 degraders. Mechanistically, BRD9 degradation was shown to specifically impact non-neuroendocrine POU2F3-positive SCLC cells by reducing chromatin accessibility preferentially at sites bearing POU2F3 DNA-binding motifs and downregulating the expression of genes associated with maintenance of the non-neuroendocrine cellular phenotype. Conversely, modulation of the mSWI/SNF complex with SMARCA4/2 ATPase inhibitors resulted in a less selective chromatin accessibility reduction and regulation of gene expression. Finally, this study demonstrated that both a clinical-grade BRD9 degrader (FHD-609) and a clinical-grade SMARCA4/2 ATPase inhibitor (FHD-286) achieved to impede tumour growth and enhance survival in POU2F3-positive SCLC xenograft models. Combining front-line chemotherapy with such targeted agents suggested an additive anti-tumour effect.

In conclusion, mSWI/SNF complex activity represents a druggable dependency in SCLC, with SMARCA4/2 inhibitors potentially addressing the broad class of POU2F3-positive SCLCs and BRD9 degraders the non-neuroendocrine POU2F3-positive SCLCs.

Atypical SCLC in light or never smokers

Traditionally, SCLC has been linked to tobacco exposure and characterised by the complete loss of bothTP53 and retinoblastoma 1 (RB1) genes. Rekhtman et-al provide clinicopathologic, genomic, and transcriptomic data to support the identification of a unique, atypical subset of SCLC that is clinically aggressive, harbours wild-type TP53 and RB1 genes, and presents in patients that are light or never smokers (Cancer Discovery 2025; doi: 10.1158/2159–8290 .CD-24-0286). At the molecular level, these atypical SCLC tumours feature a mutational phenomenon termed chromothripsis (chromosome shattering), which involves the rapid acquisition of extensive rearrangements of one or a few chromosomes after a single catastrophic event, mostly affecting chromosome 11 or 12 and giving rise to extrachromosomal DNA with amplifications or combined amplifications of oncogenes, such as cyclin D1 (CCND1) and CCND2/cyclin-dependent kinase 4 (CDK4)/mouse double minute 2 (MDM2). Notably, Rekhtman et-al reveal a unique aspect of this novel SCLC subset concerning its pathogenesis. According to their data, atypical SCLC is related to pulmonary carcinoids, which are neuroendocrine epithelial malignancies, in terms of genomics and pathology. As the authors state, this indicates that some SCLCs may be generated following a malignant transformation process arising in lower-grade neuroendocrine tumours.

The authors conclude their study by suggesting several potential therapeutic agents for atypical SCLC, including CDK4 inhibitors, MDM2 inhibitors, and temozolomide among others.

SMARCA4 as a therapeutic target for SCLC progression and treatment resistance

SCLC transcriptional subtypes display different levels of neuroendocrine differentiation and recent studies hint that one subtype may convert to another as disease progresses or resistance to chemotherapy develops, turning toward less neuroendocrine differentiated phenotypes. However, the molecular regulators of this plasticity remain elusive. This prompted Redin et al to investigate the role of SMARCA4 during subtype shift in SCLC (J Hematol Oncol 2024; doi: 10.1186/s13045-024-01572-3). Using SCLC cell lines and patient tumour databases, it was found that SMARCA4 expression shows a positive correlation with the expression of genes associated with neuroendocrine differentiation.

To understand whether SMARCA4 controls neuroendocrine cell fate, the authors employed FHD-286, a SMARCA2/SMARCA4 ATPase inhibitor, on SCLC cells and observed that this inhibition led to a lack of neuroendocrine characteristics, downregulation of neuroendocrine and neuronal signalling pathways, and potentiation of non-neuroendocrine factors. Further analysis unveiled that SMARCA4 interacts with genomic regions containing promoter sequences of genes encoding for neuroendocrine lineage transcription factors, such as neurogenic differentiation factor 1 (NEUROD1) and achaete-scute family bHLH transcription factor 1 (ASCL1), altering their chromatin accessibility and promoting neuroendocrine transcriptional programmes. Additionally, SMARCA4 was demonstrated to regulateRE1 silencing transcription factor (REST), a transcriptional repressor that blocks the neuroendocrine SCLC phenotype, through upregulating the expression of serine/arginine repetitive matrix 4 (SRRM4) responsible for splicing of REST mRNA transcripts. Aiming to identify therapeutic vulnerabilities caused by SMARCA4 inhibition in SCLC, Redin et-al discovered that SMARCA4 inactivation with FHD-286 induces the upregulation of erythroblastic leukaemia oncogene B (ERBB) signalling and, thus, turns SCLC tumours sensitive to the epidermal growth factor receptor (EGFR) inhibitor afatinib.

In summary, SMARCA4 functions to sustain the neuroendocrine phenotype and represents a promising therapeutic target in the setting of SCLC.