Shared Role for Critical Mediator Genes in Ras-Dependentand Ras-Independent Malignant Cell Transformation

Diverse types of cancer cells share a common set of critical properties that emerge in response to distinct oncogenic mutations. This suggests a role for common underlying mechanisms that mediate malignant cell transformation downstream of a variety of oncogenic drivers. Consistent with this idea, our lab has uncovered a set of genes responding synergistically to cooperating p53 and ras mutations that are critical to the cancer phenotype, and have an expression signature conserved among various types of cancers (Cooperation Response Genes, or CRGs). Using genetic models that permit modulation of oncogenic driver activities and/or identities in cancer cells, we show that the critical role of CRG expression is, at least in part, independent of the identity of given oncogenic drivers. In a conditional KrasG12D-driven model of pancreatic ductal adenocarcinoma (PDAC), the sustained loss of KrasG12D in vivo results in reductions in tumor volume commonly followed by c-Met pathway activation and tumor recurrence. In this model, CRG expression and functional relevance appear conserved together with key features of the metabolic phenotype established by Kras in the Met-driven recurrent cells. Oncogenic mutations play a continuous role in the maintenance of the cancer phenotype, and consistent with this notion expression of ~75% of CRGs tracks with ras attenuation after 3 days in vitro, in both the aforementioned PDAC model and a second independent model in which abrogation of the driving HrasG12V allele in transformed murine colon cells is achieved by cre/loxp-mediated recombination. Notably, expression of the other 25% of CRGs remains unaltered following attenuation of the primary oncogenic driver, providing evidence for hitherto unknown mechanisms which function to maintain the transformed state independently of the continuous presence of oncogenic mutations. Genetic perturbation of CRGs that are unresponsive to the alteration of oncogenic mutations resulted in tumor inhibition in secondary xenograft assays, suggesting that CRGs may represent an attractive new class of intervention targets, particularly in scenarios where molecular targeting of cancer mutations rapidly selects for treatment-resistant cancer cells that activate alternate oncogenic drivers.