Small cell lung cancer (SCLC) is a high-grade neuroendocrine malignancy with an aggressive behavior and dismal prognosis. 5-year overall survival remains a disappointing 7%. Genomically, SCLCs are homogeneous compared to non-small cell lung cancers and are characterized almost always by functional inactivation of RB1 and TP53 with no actionable mutations. Additionally, SCLCs histologically appear uniform. Thus, SCLCs are currently managed as a single disease with platinum-based chemotherapy remaining the cornerstone of treatment. Recent studies have identified expression of dominant transcriptional signatures which may permit classification of SCLCs into four biologically distinct subtypes, namely, SCLC-A, SCLC-N, SCLC-P, and SCLC-I. These groups are readily detectable by immunohistochemistry and also have potential predictive utility for emerging therapies, including PARPi, immune checkpoint inhibitors, and DLL3 targeted therapies. In contrast with their histology, studies have identified that SCLCs display both inter- and intra-tumoral heterogeneity. Identification of subpopulations of cells with high expression of PLCG2 has been linked with risk of metastasis. SCLCs also display subtype switching under therapy pressure which may contribute furthermore to metastatic ability and chemoresistance. In this review, we summarize the recent developments in the understanding of the biology of SCLCs, and discuss the potential diagnostic, prognostic, and treatment opportunities the four proposed subtypes may present for the future. We also discuss the emerging evidence of tumor heterogeneity and plasticity in SCLCs which have been implicated in metastasis and acquired therapeutic resistance seen in these aggressive tumors.
Keywords: ASCL1; DLL3; NEUROD1; PARPi; POU2F3; SLFN11; YAP1; immunotherapy; inflamed subtype; small cell lung cancer.