The typical low life expectancy and limited therapeutic options for patients with small cell lung cancer (SCLC) caused the National Cancer Institute (NCI) to categorize SCLC as “recalcitrant” cancer. SCLC-CellMiner (https://discover.nci.nih.gov/SclcCellMinerCDB) integrates drug sensitivity and genomic data from 118 patient-derived SCLC cell lines, providing a unique genomic and pharmacological resource. Transcriptomic profiling validates the SCLC consensus nomenclature based on expression of 4 master transcription factors NEUROD1, ASCL1, POU2F3 and YAP1 (NAPY classification) and demonstrate differential transcriptional networks driven by these lineage specific transcription factors. Our analyses reveal transcription networks linking SCLC subtypes with MYC and its paralogs MYCL and MYCN and inactivation of the NOTCH pathway in the neuroendocrine SCLC (N, A & P subgroups). By contrast, YAP1-driven SCLC (SCLC-Y) express the NOTCH pathway and co-express both YAP/TAZ and its negative regulator genes driving the Hippo pathway. SCLC-Y cell lines show the greatest resistance to the standard of care drugs (etoposide, cisplatin and topotecan) while PI3K-AKT-mTOR inhibitors show a higher activity in this subgroup. To explore the immune pathways and the potential value of the transciption factors based classification for selecting SCLC patients likely to respond to immune checkpoint inhibitors, we explored a transcriptome signature based on 18 established native immune response and antigen-presenting genes (APM score). The SCLC-Y cell lines are the only subset expressing innate immune response genes. SCLC-CellMiner is a powerfull tool demonstrating the value of cancer cell line genomic and pharmacological databases. Our analyses suggest the potential genomic molecular classifications to select patients for targeted therapies and immunotherapy, such as patients in the SCLC-Y subgroup who may be most responsive to immune checkpoints modulators.
Citation Format: Camille Tlemsani, Lorinc Pongor, Fathi Elloumi, Luc Girard, Kenneth Huffman, Nitin Roper, Sudhir Varma, Augustin Luna, Vinodh Rajapakse, Pascaline Boudou-Rouquette, Robin Sebastian, Kurt Kohn, Julia Krushkal, Mirit Aladjem, Beverly Teicher, Paul Meltzer, William Reinhold, John Minna, Anish Thomas, Yves Pommier. SCLC-CellMiner: An extensive cell line genomic and pharmacology resource identifies a subgroup of small cell lung cancers sensitive to targeted therapies and immunotherapies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 203.