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Targeting KRAS in pancreatic cancer

Genomic studies have identified mutations in the proto-oncogene KRAS as hallmarks in PDAC, occurring in >90% of cases. KRAS is a small GTPase that acts as a molecular switch to regulate proliferation, differentiation, metabolism, and survival. Oncogenic point mutations in KRAS result in constitutive activation of the mitogen-activated protein kinase (MAPK), PI3K, and other downstream signaling pathways. Studies in animal models have confirmed an important role of oncogenic KRAS in both tumor initiation and maintenance. Similarly, knockdown of KRAS in cancer cell lines by RNA interference (RNAi) decreases cell proliferation and/or induces apoptosis. Together, these data support targeting KRAS as a therapeutic strategy in PDAC.

Unfortunately, efforts to develop effective KRAS inhibitors have been subverted by several unique features of oncogenic KRAS including its high affinity for GTP, redundant pathways for membrane localization, and lack of deep pockets for inhibitor binding. Moreover, we have recently demonstrated that half of PDAC cell lines can survive despite CRISPR/Cas-mediated genetic ablation of KRAS, suggesting the potential for resistance to even the very best KRAS inhibitors. Surprisingly, nearly all resistant cells demonstrate induced sensitivity to PI3K inhibitors and uncover a signaling network in which PI3K regulates not only its canonical downstream target AKT but also the MAPK pathway via wild-type RAS.

Leveraging isogenic KRAS intact and deficient cells, we are pursuing several projects that may yield novel approaches to target KRAS mutant cancer cells and overcome resistance to KRAS inhibition:

  1. Validation of results from genome-wide CRISPR-based screens identifying genes demonstrating synthetic lethality with the presence of oncogenic KRAS.
  2. Understanding the mechanistic basis for PI3K signaling rewiring in the presence and absence of oncogenic KRAS.
  3. Comparing the cellular, molecular, and biochemical differences associated with expression of different KRAS mutant variants.