Comprehensive structure-function analysis reveals gain- and loss-of-function mechanisms impacting oncogenic KRAS activity.

Autor:	Kwon JJ; Department of Medical Oncology, Dana Farber Cancer Institute, Boston, MA, 02115, USA.; Harvard Medical School, Boston, MA, 02115, USA.; Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA., Dilly J; Department of Medical Oncology, Dana Farber Cancer Institute, Boston, MA, 02115, USA.; Harvard Medical School, Boston, MA, 02115, USA.; Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA., Liu S; Department of Medical Oncology, Dana Farber Cancer Institute, Boston, MA, 02115, USA.; Harvard Medical School, Boston, MA, 02115, USA., Kim E; Department of Medical Oncology, Dana Farber Cancer Institute, Boston, MA, 02115, USA.; Harvard Medical School, Boston, MA, 02115, USA.; Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA., Bian Y; Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA., Dharmaiah S; NCI RAS Initiative, Cancer Research Technology Program, Frederick National Laboratory for Cancer Research, Frederick, MD, USA., Tran TH; NCI RAS Initiative, Cancer Research Technology Program, Frederick National Laboratory for Cancer Research, Frederick, MD, USA., Kapner KS; Department of Medical Oncology, Dana Farber Cancer Institute, Boston, MA, 02115, USA.; Harvard Medical School, Boston, MA, 02115, USA., Ly SH; Department of Medical Oncology, Dana Farber Cancer Institute, Boston, MA, 02115, USA.; Harvard Medical School, Boston, MA, 02115, USA.; Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA., Yang X; Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA., Rabara D; NCI RAS Initiative, Cancer Research Technology Program, Frederick National Laboratory for Cancer Research, Frederick, MD, USA., Waybright TJ; NCI RAS Initiative, Cancer Research Technology Program, Frederick National Laboratory for Cancer Research, Frederick, MD, USA., Giacomelli AO; Humber Polytechnic, Toronto, ON, Canada., Hong AL; Department of Pediatrics, Emory University School of Medicine and Children's Healthcare of Atlanta, Atlanta, GA, USA., Misek S; Department of Medical Oncology, Dana Farber Cancer Institute, Boston, MA, 02115, USA.; Harvard Medical School, Boston, MA, 02115, USA.; Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA., Wang B; Department of Medical Oncology, Dana Farber Cancer Institute, Boston, MA, 02115, USA.; Harvard Medical School, Boston, MA, 02115, USA.; Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA., Ravi A; Department of Medical Oncology, Dana Farber Cancer Institute, Boston, MA, 02115, USA.; Harvard Medical School, Boston, MA, 02115, USA.; Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA., Doench JG; Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA., Beroukhim R; Department of Medical Oncology, Dana Farber Cancer Institute, Boston, MA, 02115, USA.; Harvard Medical School, Boston, MA, 02115, USA.; Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA., Lemke CT; Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA., Haigis KM; Department of Medical Oncology, Dana Farber Cancer Institute, Boston, MA, 02115, USA.; Harvard Medical School, Boston, MA, 02115, USA.; Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA., Esposito D; NCI RAS Initiative, Cancer Research Technology Program, Frederick National Laboratory for Cancer Research, Frederick, MD, USA., Root DE; Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA., Nissley DV; NCI RAS Initiative, Cancer Research Technology Program, Frederick National Laboratory for Cancer Research, Frederick, MD, USA., Stephen AG; NCI RAS Initiative, Cancer Research Technology Program, Frederick National Laboratory for Cancer Research, Frederick, MD, USA., McCormick F; NCI RAS Initiative, Cancer Research Technology Program, Frederick National Laboratory for Cancer Research, Frederick, MD, USA.; University of California, San Francisco Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA, USA., Simanshu DK; NCI RAS Initiative, Cancer Research Technology Program, Frederick National Laboratory for Cancer Research, Frederick, MD, USA., Hahn WC; Department of Medical Oncology, Dana Farber Cancer Institute, Boston, MA, 02115, USA.; Harvard Medical School, Boston, MA, 02115, USA.; Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA., Aguirre AJ; Department of Medical Oncology, Dana Farber Cancer Institute, Boston, MA, 02115, USA.; Harvard Medical School, Boston, MA, 02115, USA.; Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA.
Jazyk:	angličtina
Zdroj:	BioRxiv : the preprint server for biology [bioRxiv] 2024 Oct 25. Date of Electronic Publication: 2024 Oct 25.
DOI:	10.1101/2024.10.22.618529
Abstrakt:	To dissect variant-function relationships in the KRAS oncoprotein, we performed deep mutational scanning (DMS) screens for both wild-type and KRAS G12D mutant alleles. We defined the spectrum of oncogenic potential for nearly all possible KRAS variants, identifying several novel transforming alleles and elucidating a model to describe the frequency of KRAS mutations in human cancer as a function of transforming potential, mutational probability, and tissue-specific mutational signatures. Biochemical and structural analyses of variants identified in a KRAS G12D second-site suppressor DMS screen revealed that attenuation of oncogenic KRAS can be mediated by protein instability and conformational rigidity, resulting in reduced binding affinity to effector proteins, such as RAF and PI3-kinases, or reduced SOS-mediated nucleotide exchange activity. These studies define the landscape of single amino acid alterations that modulate the function of KRAS, providing a resource for the clinical interpretation of KRAS variants and elucidating mechanisms of oncogenic KRAS inactivation for therapeutic exploitation.
Databáze:	MEDLINE
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