Abstract PO-099: SOX2 delineates a mouse lung adenocarcinoma subtype vulnerable to targeted therapy

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. We leveraged transcriptional data from >800 early-stage and advanced patients to classify tumors based on signaling similarities and discover subgroups within this unmet patient population. 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. We identified differential subtype response to MEK inhibition across multiple preclinical model systems and a clinical trial, supporting prognostic utility of transcriptional subtyping. Differential subtype dependency on MEK signaling reproduced in a mouse model of KRAS-mutant lung adenocarcinoma, where a MEK-dependent adenocarcinoma subtype is driven by a SOX2 cellular state. Our findings support forward translational relevance of transcriptional subtypes and reveal that naturally evolved yet ectopic expression of a pioneer transcription factor may modulate tumor subtype and response. Citation Format: Jonathan E. Cooper, Anneleen Daemen, Dorothee Nickles, Szymon Myrta, Oded Foreman, Jeff Eastham, Melissa R. Junttila, Heinrich Jasper. SOX2 delineates a mouse lung adenocarcinoma subtype vulnerable to targeted therapy [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-099.