Abstract
Pancreatic ductal adenocarcinoma (PDAC) is among the deadliest cancers with a dismal 7% 5-year survival rate and is projected to become the second leading cause of cancer-related deaths by 2020. KRAS is mutated in 95% of PDACs and is a well-validated driver of PDAC growth and maintenance. However, despite comprehensive efforts, an effective anti-RAS drug has yet to reach the clinic. Different paths to inhibiting RAS signaling are currently under investigation in the hope of finding a successful treatment. Recently, direct RAS binding molecules have been discovered, challenging the perception that RAS is an “undruggable” protein. Other strategies currently being pursued take an indirect approach, targeting proteins that facilitate RAS membrane association or downstream effector signaling. Unbiased genetic screens have identified synthetic lethal interactors of mutant RAS. Most recently, metabolic targets in pathways related to glycolytic signaling, glutamine utilization, autophagy, and macropinocytosis are also being explored. Harnessing the patient’s immune system to fight their cancer is an additional exciting route that is being considered. The “best” path to inhibiting KRAS has yet to be determined, with each having promise as well as potential pitfalls. We will summarize the state-of-the-art for each direction, focusing on efforts directed toward the development of therapeutics for pancreatic cancer patients with mutated KRAS.
Highlights
Mutant KRAS Drives PDAC Development and Maintenance90% of pancreatic cancers are pancreatic ductal adenocarcinoma (PDAC), which is almost universally fatal [1]
7% 5-year survival rate and is projected to become the second leading cause of cancer-related deaths by 2020
KRAS protein function is critical for pancreatic ductal adenocarcinoma (PDAC) growth and maintenance [8,9,10], the Pancreatic Cancer
Summary
90% of pancreatic cancers are pancreatic ductal adenocarcinoma (PDAC), which is almost universally fatal [1]. Recent exome sequencing has provided a detailed genetic profile of PDAC, with mutational activation of the KRAS oncogene found in ~95% of patients [4,5,6,7]. KRAS protein function is critical for PDAC growth and maintenance [8,9,10], the Pancreatic Cancer. The RAS family of small GTPases includes three genes: HRAS, NRAS, and KRAS. These three loci encode four different protein isoforms: HRAS, NRAS, KRAS4A, and KRAS4B. All of the isoforms are similar in the amino acid sequence of the G domain (~80%) with major differences being restricted to the Cancers 2016, 8, 45; doi:10.3390/cancers8040045 www.mdpi.com/journal/cancers.
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