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 Nature cell biology
Vol 20
Issue 9
Date 2018 Sep
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.

Filtering

  • Case insensitive filtering will display rows where any text in any cell matches the filter term
  • Simple literal full or partial string matches
  • Separate multiple filter terms with a spaces, order doesn't matter (a b c and c b a are equivalent )
  • Filtering will only apply to rows that are already loaded on the page, filtering has no impact on query parameters
  • Use quotes to match a longer phrase which contains spaces "mtor c1483f"

Sorting

  • Generally, the default sort order for tables is set to be first column ascending, however, specific tables may set a different default sort order.
  • Click on any column header arrows to sort by that column
  • Hold down the Shift key and click multiple columns to sort by more than one column, be sure to set ascending or descending order for a given column, before moving on to the next column.

Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Therapy Description
RMC-4550 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).
Drug Name Trade Name Synonyms Drug Classes Drug Description
RMC-4550 SHP2 Inhibitor 6 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).
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
KRAS G12C esophageal cancer predicted - sensitive RMC-4550 Preclinical - Cell culture Actionable In a preclinical study, RMC-4550 inhibited growth of esophageal cancer cells harboring KRAS G12C in 3D culture (PMID: 30104724). 30104724
KRAS G12D colon cancer predicted - resistant RMC-4550 Preclinical - Cell culture Actionable In a preclinical study, RMC-4550 did not inhibit growth of colon cancer cells harboring KRAS G12D in 3D culture (PMID: 30104724). 30104724
KRAS Q61K gastric adenocarcinoma predicted - resistant RMC-4550 Preclinical - Cell culture Actionable In a preclinical study, RMC-4550 did not inhibit growth of gastric adenocarcinoma cells harboring KRAS Q61K in 3D culture (PMID: 30104724). 30104724
KRAS G12C non-small cell lung carcinoma 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 KRAS G12C (PMID: 30104724). 30104724
KRAS G12V colon cancer predicted - resistant RMC-4550 Preclinical - Cell culture Actionable In a preclinical study, RMC-4550 did not inhibit growth of colon cancer cell lines harboring KRAS G12V in 3D culture (PMID: 30104724). 30104724
BRAF N581D non-small cell lung 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
KRAS G13D colorectal cancer predicted - resistant RMC-4550 Preclinical - Cell line xenograft Actionable In a preclinical study, RMC-4550 did not inhibit growth of colorectal cancer cell lines harboring KRAS G13D in 3D culture, and did not inhibit tumor growth in cell line xenograft models (PMID: 30104724). 30104724
KRAS G12V lung cancer predicted - sensitive RMC-4550 Preclinical - Cell culture Actionable In a preclinical study, RMC-4550 inhibited growth in 2 of 3 lung cancer cell lines harboring KRAS G12V in 3D 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
KRAS G12V lung small cell carcinoma predicted - resistant RMC-4550 Preclinical - Cell culture Actionable In a preclinical study, RMC-4550 did not inhibit growth of lung small cell cancer cells harboring KRAS G12V in 3D culture (PMID: 30104724). 30104724
KRAS G12C lung cancer sensitive RMC-4550 Preclinical - Cell line xenograft Actionable In a preclinical study, RMC-4550 decreased RAS-GTP level, inhibited Erk phosphorylation and proliferation of lung cancer cell lines harboring KRAS G12C in culture, resulted in dose-dependent tumor growth inhibition in cell line xenograft models (PMID: 30104724). 30104724
KRAS G13D lung cancer predicted - resistant RMC-4550 Preclinical - Cell culture Actionable In a preclinical study, RMC-4550 did not inhibit growth of colorectal cancer cells harboring KRAS G13D in 3D culture (PMID: 30104724). 30104724
BRAF D594N non-small cell lung 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
KRAS G12D lung cancer predicted - resistant RMC-4550 Preclinical - Cell culture Actionable In a preclinical study, RMC-4550 did not inhibit growth of lung cancer cells harboring KRAS G12D in 3D culture (PMID: 30104724). 30104724
KRAS Q61H lung cancer predicted - resistant RMC-4550 Preclinical - Cell culture Actionable In a preclinical study, RMC-4550 did not inhibit growth of lung cancer cell lines harboring KRAS Q61H in 3D culture (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
KRAS Q61X Advanced Solid Tumor predicted - resistant RMC-4550 Preclinical - Cell culture Actionable In a preclinical study, RMC-4550 did not inhibit growth of cancer cell lines harboring KRAS Q61X (H,K,L) mutations in 3D culture (PMID: 30104724). 30104724
BRAF G596R PTPN11 E76K colorectal cancer resistant RMC-4550 Preclinical - Cell culture Actionable In a preclinical study, expression of PTPN11 E76K in colorectal cancer cells harboring BRAF G596R abolished their sensitivity to RMC-4550-induced inhibition of Erk phosphorylation and proliferation in culture (PMID: 30104724). 30104724
KRAS G12V pancreatic cancer predicted - resistant RMC-4550 Preclinical - Cell culture Actionable In a preclinical study, RMC-4550 did not inhibit growth of pancreatic cancer cells harboring KRAS G12V in 3D culture (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
KRAS G12D pancreatic cancer predicted - resistant RMC-4550 Preclinical - Cell culture Actionable In a preclinical study, RMC-4550 did not inhibit growth of pancreatic cancer cells harboring KRAS G12D in 3D culture (PMID: 30104724). 30104724
KRAS G13D Advanced Solid Tumor predicted - resistant RMC-4550 Preclinical - Cell line xenograft Actionable In a preclinical study, RMC-4550 did not inhibit growth of cancer cell lines harboring KRAS G13D in 3D culture, and did not inhibit tumor growth in cell line xenograft models (PMID: 30104724). 30104724
KRAS G12A lung cancer sensitive RMC-4550 Preclinical - Cell culture Actionable In a preclinical study, RMC-4550 inhibited proliferation of lung cancer cell lines harboring KRAS G12A in 3D culture (PMID: 30104724). 30104724
KRAS Q61L colon cancer predicted - resistant RMC-4550 Preclinical - Cell culture Actionable In a preclinical study, RMC-4550 did not inhibit growth of colon cancer cells harboring KRAS Q61L in 3D culture (PMID: 30104724). 30104724
KRAS G12D colorectal cancer predicted - sensitive RMC-4550 Preclinical - Cell culture Actionable In a preclinical study, RMC-4550 inhibited growth of colorectal cancer cells harboring KRAS G12D in 3D culture (PMID: 30104724). 30104724
KRAS G12S lung cancer predicted - resistant RMC-4550 Preclinical - Cell culture Actionable In a preclinical study, RMC-4550 did not inhibit growth of lung cancer cells harboring KRAS G12S in 3D culture (PMID: 30104724). 30104724
KRAS G12C pancreatic cancer sensitive RMC-4550 Preclinical - Cell line xenograft Actionable In a preclinical study, RMC-4550 decreased RAS-GTP level, inhibited Erk phosphorylation and proliferation of pancreatic cancer cells harboring KRAS G12C in culture, resulted in dose-dependent tumor growth inhibition in cell line xenograft models (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
KRAS G12C rectum cancer predicted - sensitive RMC-4550 Preclinical - Cell culture Actionable In a preclinical study, RMC-4550 inhibited growth of rectal cancer cells harboring KRAS G12C in 3D culture (PMID: 30104724). 30104724
KRAS Q61K lung cancer predicted - resistant RMC-4550 Preclinical - Cell culture Actionable In a preclinical study, RMC-4550 did not inhibit growth of lung cancer cells harboring KRAS Q61K in 3D culture (PMID: 30104724). 30104724