The effects of Gly12 KRAS oncogenes are mutation and context specific

Abstract

Activating mutations in the KRAS oncogene are frequent across cancers and contribute to a malignant phenotype by dysregulating cell growth and promoting tumorigenesis. As these mutations are key drivers involved in the tumorigenesis of some of the deadliest cancers – colorectal cancer (CRC), non-small cell lung cancer (NSCLC), and pancreatic adenocarcinoma (PDAC) – there have been intense efforts to therapeutically target KRAS proteins and their downstream signaling effectors, with limited success. Within the field, we are slowly coming to appreciate the notion that KRAS signaling is context dependent, and that several factors can impact the therapeutic targeting of these cancers, as seen with the unequal response to KRASG12C inhibitors between NSCLC and CRC patients. Here, we investigate how context affects oncogenic KRAS driven tumorigenesis, turning to mouse models to overcome the genetic heterogeneity of human tumors. At the level of tissues, we find K-RasG12D-driven signaling networks are distinct between colon and pancreas tumors. Furthermore, using humanized mouse proteomic networks, we prioritize KRASG12D genetic dependencies identified from DepMap, and identify ASL as a KRASG12D genetic dependency in CRC. In addition to studying tissue level differences, we compare the effects of K-RasG12D, K-RasG12C, and K-RasG12V in mouse colon epithelium and tumors to study allele-level differences. Though we observe no strong phenotypic differences between the mutants, transcriptomic and proteomic analyses reveal a gradient of activation of immunosuppressive pathways among mutants, correlating with mouse survival differences. In addition, we identify a K-RasG12C specific activation of Notch and Hedgehog signaling pathways, which can potentially be co-targeted in KRASG12C mutant colon tumors with G12C inhibitors. Furthermore, in the context of KRASG12C inhibitors, we find that the activation of Wnt signaling in the context of colon tumors may impair the efficacy of these inhibitors. Taken together, the work presented in this thesis demonstrates that the effects of oncogenic KRAS are shaped not only by the mutation itself, but the genetic context in which it is found, and that these factors can influence the therapeutic targeting of KRAS-driven cancers.