Reference Detail

Ref Type

Journal Article

PMID

(30104724)

Authors

Nichols RJ, Haderk F, Stahlhut C, Schulze CJ, Hemmati G, Wildes D, Tzitzilonis C, Mordec K, Marquez A, Romero J, Hsieh T, Zaman A, Olivas V, McCoach C, Blakely CM, Wang Z, Kiss G, Koltun ES, Gill AL, Singh M, Goldsmith MA, Smith JAM, Bivona TG

Title

RAS nucleotide cycling underlies the SHP2 phosphatase dependence of mutant BRAF-, NF1- and RAS-driven cancers.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Nature cell biology	20	9	2018 Sep	1064-1073	Nat Cell Biol

URL

Abstract Text

Oncogenic alterations in the RAS/RAF/MEK/ERK pathway drive the growth of a wide spectrum of cancers. While BRAF and MEK inhibitors are efficacious against BRAFV600E-driven cancers, effective targeted therapies are lacking for most cancers driven by other pathway alterations, including non-V600E oncogenic BRAF, RAS GTPase-activating protein (GAP) NF1 (neurofibromin 1) loss and oncogenic KRAS. Here, we show that targeting the SHP2 phosphatase (encoded by PTPN11) with RMC-4550, a small-molecule allosteric inhibitor, is effective in human cancer models bearing RAS-GTP-dependent oncogenic BRAF (for example, class 3 BRAF mutants), NF1 loss or nucleotide-cycling oncogenic RAS (for example, KRASG12C). SHP2 inhibitor treatment decreases oncogenic RAS/RAF/MEK/ERK signalling and cancer growth by disrupting SOS1-mediated RAS-GTP loading. Our findings illuminate a critical function for SHP2 in promoting oncogenic RAS/MAPK pathway activation in cancers with RAS-GTP-dependent oncogenic BRAF, NF1 loss and nucleotide-cycling oncogenic KRAS. SHP2 inhibition is a promising molecular therapeutic strategy for patients with cancers bearing these oncogenic drivers.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials
RMC-4550	RMC-4550	20	0

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
RMC-4550		RMC4550\|RMC 4550	SHP2 Inhibitor 20	RMC-4550 is a small molecule allosteric inhibitor of Shp2 that blocks Ras-Raf-Mek-Erk pathway signaling, leading to tumor growth inhibition (PMID: 30104724).

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
BRAF D594N	lung non-small cell carcinoma	predicted - sensitive	RMC-4550	Preclinical - Pdx	Actionable	In a preclinical study, RMC-4550 treatment resulted in decreased Erk phosphorylation and dose-dependent tumor growth inhibition in patient-derived xenograft (PDX) models of non-small cell lung cancer harboring BRAF D594N (PMID: 30104724).	30104724
BRAF G596R	colorectal cancer	predicted - sensitive	RMC-4550	Preclinical - Cell culture	Actionable	In a preclinical study, RMC-4550 inhibited Erk phosphorylation and proliferation of colorectal cancer cells harboring BRAF G596R in culture (PMID: 30104724).	30104724
BRAF N581D	lung non-small cell carcinoma	predicted - sensitive	RMC-4550	Preclinical - Pdx	Actionable	In a preclinical study, RMC-4550 treatment resulted in dose-dependent tumor growth inhibition in patient-derived xenograft (PDX) models of non-small cell lung cancer harboring BRAF N581D (PMID: 30104724).	30104724
BRAF G469A	lung cancer	resistant	RMC-4550	Preclinical - Cell culture	Actionable	In a preclinical study, RMC-4550 did not inhibit Erk phosphorylation or proliferation of lung cancer cells harboring BRAF G469A in culture (PMID: 30104724).	30104724
BRAF V600E	melanoma	resistant	RMC-4550	Preclinical - Cell culture	Actionable	In a preclinical study, RMC-4550 did not inhibit Erk phosphorylation or proliferation of melanoma cells harboring BRAF V600E in culture (PMID: 30104724).	30104724
BRAF G466V	lung cancer	predicted - sensitive	RMC-4550	Preclinical - Cell culture	Actionable	In a preclinical study, RMC-4550 inhibited Erk phosphorylation and proliferation of lung cancer cells harboring BRAF G466V in culture (PMID: 30104724).	30104724