Abstract 5112: Tumor cell expression of a distinct TME gene signature defines differential drug sensitivities to EGFR/MEK/SRC targeted agents

Abstract Recently, we serendipitously identified a pair of distinct 10-gene signatures, one associated with epithelial cells (EPIS) and one the tumor microenvironment(TMES). When we classified 2373 colorectal cancer (CRC) tumors into the consensus molecular subtypes (CMS1-4), the EPIS signature score was predominantly related to the TME-poor CMS2/CMS3 classes and was highly predictive of EGFRi outcomes in two clinical trial datasets and a large, real-world clinico-genomics dataset. By contrast, the TMES signature score was strongly associated with the immune/stromal CMS1/CMS4 subtypes and was highly correlated with the gene expression signature scores portending EMT, SRC activation and MEK inhibitor resistance (MEKi-R). To understand the cellular features underpinning the TMES correlation, we further analyzed the cellular origins of 61 SRC signature genes and 13 MEKi-R signature genes, as well as 8 EMT genes using an independent public scRNASEQ dataset (n=62). All of the 13 MEKi-R genes and all of the 8 EMT genes, as well as most of the SRC activation genes, were predominantly expressed in various immune/stromal TME cells, supporting a key role of the TME gene expression. Remarkably, when the signature scores were analyzed in a dataset of ∼150 heterogenous CRC cell lines that do not have a TME, a similar strong correlation among the TMES, EMT, SRC activation and MEKi-R scores was also observed. These data suggest that the CRC epithelial cells may have adopted the TME gene expression features important in modulating the drug sensitivities. Spatial transcriptomics of 8 CRC samples confirmed that the EPIS genes were predominantly expressed in epithelial cells. By contrast, the signature genes of the TMES linked to EMT/SRC activation/MEKi-R were diffusely expressed across epithelial/invasive cancer mixed with the TME, indicating an interactive tumor-TME cellular feature. Our data suggest that the TME through its impact on epithelial cell gene expression may define drug sensitivities to targeted therapies. Citation Format: Mingli Yang, Michael V. Nebozhyn, Lance Pflieger, Ramani Soundararajan, Michelle Maurin, Heiman Wang, Andrey Loboda, W. Jack Pledger, Timothy J. Yeatman. Tumor cell expression of a distinct TME gene signature defines differential drug sensitivities to EGFR/MEK/SRC targeted agents [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5112.