Exploring the influence of intra-tumor heterogeneity on drug resistance in KRAS drivenpancreatic cancer

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The KRAS oncogene is mutated in more than 95% of pancreatic ductal adenocarcinoma (PDAC) and a well-validated driver of PDAC growth. However, the effectiveness of direct targeting of oncogenic KRAS or indirect inhibition of KRAS effector signaling is limited by treatment-induced onset of drug resistance, resulting in treatment failure. Resistance is driven by tumor cell heterogeneity and the outgrowth of de novo resistant variant subpopulations. Although PDAC inter-tumor genetic heterogeneity is well-documented, intra-tumor heterogeneity has not been studied and how this may impact KRAS signaling, and consequently, response to signaling inhibition, are important issues not yet understood. In the proposed study I will explore intra-tumor heterogeneity in recently developed PDAC patient-derived three-dimensional organoid cultures. These cultures model cancer more accurately than conventional two-dimensional cell culture models. I will monitor the fitness landscape shaped by heterogeneity of the cancer cells and their changes upon KRAS suppression and signaling inhibition. To accomplish this, I will apply advanced methodologies that will allow me to analyze PDAC organoids at the single cell level. This includes profiling genomic mutations, gene transcription and effector signaling. My study will guide the development of therapeutic strategies to overcome tumor cell heterogeneity to achieve a more effective and long-term response to anti-KRAS treatment strategies.