KRAS Mutant Pancreatic Cancer: No Lone Path to an Effective Treatment: Beyond the Abstract

The activation of a RAS oncogene drives approximately 25% of all human cancers, including the three most deadly cancers in the United States, lung, colon, and pancreas cancer. The KRAS gene is mutated in ~95% of pancreatic cancers, and it is well-validated as a driver of both growth and maintenance of this disease.

Our laboratory specifically focuses on pancreatic cancer because progress towards treating this disease has been minimal and it has a dismal 5-year survival rate of ~7%.  Clinically, this cancer is difficult to detect because of the generality of symptoms it presents, the location of the pancreas deep within the abdomen, and the lack of a diagnostic screening test. Surgery is currently the only effective treatment option, but most patients present with metastatic disease and do not qualify for surgery. Treatment options are lacking and it’s widely accepted that the development of therapies to block mutant KRAS protein function would make significant strides in improving the survival and quality of life of pancreatic cancer patients.

In this review we discuss different strategies aimed at inhibiting KRAS mutant pancreatic cancers including inhibiting KRAS directly, targeting downstream effectors, preventing plasma membrane association, exploiting metabolic targets, and harnessing the immune system. Perhaps the most successful approach thus far has been the development of inhibitors of downstream effectors in the RAF-MEK-ERK and PI3K-AKT-mTOR pathways, many of which are kinases and are more easily druggable. Although these inhibitors were successful pre-clinically, they have been largely unsuccessful as monotherapies in clinical trials. The failure of successful preclinical treatments in humans is largely due to the cancers adapting and developing resistance. We suggest that treatments combining multiple discussed strategies may produce effective cocktails and make it more difficult for cells to develop resistance.

The 30-year long battle against drugging KRAS has yielded underwhelming options for pancreatic cancer patients. This has prompted the National Cancer Institute to initiate the RAS Initiative, to stimulate new ideas and directions for the field. There are many exciting avenues for KRAS drug discovery including unearthing new signaling connections in the areas of metabolism and immunology. Once better understood, specific therapies can be designed to kill KRAS signaling and thwart pancreatic cancer.

Written By: Daniel Zeitouni and Kirsten L. Bryant