Subtype-specific transcription factors are clinically relevant and show distinct therapeutic vulnerabilities in human small cell lung cancer

Abstract

<b>Background:</b> Key transcription factors ASCL1, NEUROD1, POU2F3, YAP1 have been recently reported to characterize uniquely different small cell lung cancer (SCLC) subtypes (SCLC-A; SCLC-N; SCLC-P; SCLC-Y). However, their clinical presence and therapeutic relevance has not yet been widely investigated. <b>Methods:</b> Immunohistochemistry (IHC) was performed on surgically resected specimens of n=386 SCLC patients. Furthermore, large-scale proteomic and in-depth bioinformatical analyses were conducted in n=26 human SCLC cell lines. Standard-of care and targeted agents were used to evaluate distinct therapeutic vulnerabilities in vitro. <b>Results:</b> IHC revealed SCLC-A (ASCL1-dominant), SCLC-AN (combined ASCL1/NEUROD1), SCLC-N (NEUROD1-dominant), SCLC-P (POU2F3-dominant) and quadruple-negative SCLC specific subtypes (SCLC-QN) to be present in surgically resected SCLC specimens. Interestingly, SCLC-A subtype significantly correlated with poor and SCLC-P subtype with favorable clinical outcome. Proteomic pathway enrichment analysis identified unique expressional signatures for each SCLC subtype. Cell viability assays demonstrated remarkable sensitivity and resistance differences to standard-of-care chemotherapeutics and targeted agents between distinct SCLC subtypes. <b>Conclusions:</b> Differential expression signatures of four key-transcription factors ASCL1, NEUROD1, POU2F3 and YAP1 are present and clinically relevant in SCLC. Our findings may contribute to a better insight into the biology and therapeutic diversity of SCLC.