Recent Progress in Drugging the ‘Undruggable’ RAS Oncogene

Thursday April 29, 2021

1:30 pm - 3:00 pm Eastern Time (ET)

View session on the EB Virtual Platform (EB registration required)

DCP DDD MP

Chair :

Christine Canman
University of Michigan

Kirsten Bryant
University of North Carolina at Chapel Hill



The KRAS oncogene has always been thought to be undruggable and one of the Holy Grails of targeted cancer therapy. This symposium will highlight new approaches to selectively target mutant KRAS-dependent cancers ranging from the identification of novel allosteric regions of RAS important for signaling that ultimately could be targeted by small molecule inhibitors and new combination therapy strategies designed to exploit vulnerabilities of KRAS-dependent cancers or reverse immune suppression in the tumor microenvironment.

Speakers

John O'Bryan - Medical University of South Carolina

Inhibiting the “Undruggable” RAS: Identification of Novel Allosteric and Enzymatic Vulnerabilities

Dr. O’Bryan will discuss using Monobody technology to identify critical allosteric regions important for wild type and mutant RAS activity. His research is revealing new complexities of RAS signaling in addition to identifying new regions of RAS that can be targeted by small molecule inhibitors.

Kirsten Bryant - University of North Carolina at Chapel Hill

Combination Approaches for Targeting Autophagy in RAS Mutant Cancers

Inhibiting the ERK MAPK pathway or autophagy alone has been ineffective in treating KRAS driven pancreatic cancer. Dr. Bryant’s research revealed that inhibiting ERK creates an unappreciated metabolic vulnerability – increased dependence on autophagic flux, which can be exploited with combination therapy of MEK or ERK inhibitors and chloroquine, an inhibitor of lysosomal acidification. This potential new approach to treating pancreatic cancer and is currently being evaluated in clinical trials. The Bryant Lab’s current work is aimed at determining additional sensitizers to anti-autophagy therapies, as well as new inhibitors of the autophagy pathway.

Judith Sebolt-Leopold - University of Michigan

Outsmarting Mutant RAS through Precision Polypharmacology

Dr. Leopold will discuss a drug development strategy to target two oncogenic drivers, EGFR and PI3K, implicated in resistance of KRAS mutant tumors to molecular targeted therapies. Her research has identified a small molecule approach to selectively impair signaling of both of these critical kinases in a single molecule to render KRAS mutant cancers sensitive to MEK inhibition. MTX-211, a rationally designed first-in-class highly selective dual inhibitor of PI3K and EGFR kinases, has been shown to attack KRAS oncogenic signaling.

Marcus Ruscetti - University of Massachusetts Medical School

Harnessing Cellular Senescence to Restore Anti-tumor Immune Surveillance in KRAS Mutant Tumors

Dr. Ruscetti will discuss his previous and ongoing research characterizing a new approach to treating K-RAS dependent pancreatic cancer: targeting MEK and CDK4/6 simultaneously. Inhibiting both pathways not only suppresses pancreatic cancer cell proliferation but also induces changes in the tumor microenvironment through a process called cellular senescence that lead to new susceptibilities to existing chemo- and immunotherapy regimens. He will touch on his recent work investigating the intrinsic and extrinsic regulation of senescence and ways to harness its ability to remodel tumor microenvironments to overcome immune suppression and potentiate immunotherapy in pancreas cancer and other RAS-driven malignancies.

Last Updated: February 8, 2021
Key Dates
 
April 27 – 30, 2021

ASPET Annual Meeting at EB 2021

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