Small cell lung cancer (SCLC) can be divided into three specific molecular subgroups in terms of clinical behaviour, European researchers have shown.
Differential expression of the subtype-specific proteins ASCL1, NEUROD1, and POU2F3 in tumour tissue defines biologically distinct SCLC subtypes that also have different disease outcomes in response to drug therapies , according to a multicentre study led by a team from Medical University of Vienna, Austria.
Their findings, published in the Journal of Pathology are based on immunohistochemistry (IHC) analysis of surgically resected tumour samples from 386 patients with SCLC, followed by investigation of subtype-specific therapeutic vulnerabilities in a proteomics study combined with in vitro cytotoxicity assays in a large panel of human SCLC cell lines.
The analysis found that in addition to the classic SCLC-A (ASCL1-dominant) subtype there were variations such as SCLC-AN (combined ASCL1/NEUROD1), SCLC-N (NEUROD1-dominant) and SCLC-P (POU2F3-dominant) types of SCLC and also a quadruple-negative SCLC subtype (SCLC-QN).
The highest overall survival rates were associated with non-neuroendocrine subtypes (SCLC-P and SCLC-QN) and the lowest with neuroendocrine subtypes (SCLC-A, SCLC-N, SCLC-AN).
High ASCL1 expression was associated with poor prognosis and high POU2F3 expression with good prognosis. Notably, high ASCL1 expression influenced survival outcomes independently of other variables in a multivariate model.
The researchers noted that some subtypes respond differently to chemotherapeutics and targeted drugs. High POU2F3 and YAP1 protein abundances correlated with sensitivity and resistance to standard-of-care chemotherapeutics, respectively.
Specific correlation patterns were also found between the efficacy of targeted agents and subtype-specific protein abundances.