Miguel Bronchud, Veteran Cancer Clinician and Researcher and Co-Founder of Regenerative Medicine Solutions, shared on LinkedIn:
“KRAS is a key signaling protein that transmits extracellular signals to downstream pathways by recruiting numerous effector proteins.
In the established model, the active GTP-bound KRAS directly interacts with effector proteins (e.g., RAF kinases and PI3K), triggering downstream signaling including the mitogen-activated protein kinase (MAPK) and PI3K pathways.
Intrinsic GTP hydrolysis activity possessed by KRAS, along with the regulatory actions of GTPase-activating proteins (GAPs), facilitates the hydrolysis of GTP, converting activated KRAS into its inactive, GDP-bound form.
This negative regulation ensures the KRAS-mediated signaling cascade in normal cells is precisely controlled, but KRAS mutation occurs in 31.2% of all human cancers, especially the three most lethal cancer types (78.7% in pancreatic cancer, 49.7% in colorectal cancer, 20.1% in lung cancer)
Mutant KRAS remains predominantly in the active GTP-bound state due to impaired intrinsic GTPase function and reduced sensitivity to negative regulation by GAPs, leading to constitutive activation of pro-neoplastic signaling and malignant transformation .
Although once deemed ‘undruggable’, KRAS has now emerged as a viable drug target with two FDA-approved therapies targeting KRASG12C and more under clinical development.
Title: Dynamic remodeling of the KRAS interactome by direct RAS inhibitors with distinct mechanism of action reveals convergent responses
Authors: Yang Yang, Tingyu Liu, Charles Y. Cho, Xianzhong Liu, Ansgar Brock, Doug Quackenbush, Kaisheng Chen, Frederick Lo, Cyril H. Benes, Jacob R. Haling
Druggability of KRAS was first demonstrated by covalent KRASG12C inhibitors targeting the Switch II pocket and further reaffirmed by two classes of recently designed inhibitors:
- The noncovalent Switch II binders induce conformational changes in the KRAS Switch I and II loops, which are critical for recruiting downstream effectors, exemplified by MRTX1133 disrupting the KRASG12D-GTP-RAF1 complex
- The cyclophilin A recruiters, such as RMC-6236, form a ternary complex with RAS and CYPA to directly occlude the binding surface of active GTP-KRAS.
Authors from Novartis Biomedical Research, San Diego, CA, USA now explore and describe the impact of RAS inhibition on the KRAS interactome using Proximity-dependent Biotin Identification.”
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