Tumor Cell Expression of a Distinct TME Gene Signature Defines Differential Drug Sensitivities to EGFR/MEK/SRC Targeted Agents

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. 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.