Abstract PO-101: Transcriptional heterogeneity in lung adenocarcinoma reveals distinct therapeutic vulnerabilities

Lung adenocarcinomas comprise the largest fraction of non-small cell lung cancer, which is the leading cause of cancer deaths. 75% of adenocarcinomas lack targeted therapies due to scarcity of druggable drivers. Here we leverage transcriptional data from >800 early-stage and advanced patients to classify tumors based on signaling similarities and discover subgroups within this unmet patient population. We identify three robust subtypes dubbed Mucinous, Proliferative, and Mesenchymal with respective pathway phenotypes. These transcriptional states lack discrete and causative mutational etiology as evidenced by similarly distributed oncogenic drivers including KRAS and EGFR. The subtypes capture heterogeneity even amongst tumors lacking known oncogenic drivers. Paired multi-regional intratumoral biopsies demonstrate unified subtypes despite divergently evolved pro-oncogenic mutations, indicating subtype stability during selective pressure. Heterogeneity amongst in vitro and in vivo preclinical models is expounded by the human lung adenocarcinoma subtypes and can be leveraged to discover subtype-specific vulnerabilities. As proof-of-concept, we identify differential subtype response to MEK pathway inhibition in a chemical library screen of 89 lung cancer cell lines, which reproduces across model systems and a clinical trial, supporting prognostic utility of transcriptional subtyping. Our findings support forward translational relevance of transcriptional subtypes, where further exploration therein may improve lung adenocarcinoma treatment. Citation Format: Anneleen Daemen, Jonathan E. Cooper, Szymon Myrta, Matthew J. Wongchenko, Eva Lin, Jason E. Long, Oded Foreman, Zora Modrusan, Jarrod Tremayne, Cecile C. de la Cruz, Mark Merchant, Scott E. Martin, Yibing Yan, Melissa R. Junttila. Transcriptional heterogeneity in lung adenocarcinoma reveals distinct therapeutic vulnerabilities [abstract]. In: Proceedings of the AACR Virtual Special Conference on Tumor Heterogeneity: From Single Cells to Clinical Impact; 2020 Sep 17-18. Philadelphia (PA): AACR; Cancer Res 2020;80(21 Suppl):Abstract nr PO-101.