Reference Detail

Ref Type Journal Article
PMID (27422710)
Authors Kim JY, Welsh EA, Fang B, Bai Y, Kinose F, Eschrich SA, Koomen JM, Haura EB
Title Phosphoproteomics Reveals MAPK Inhibitors Enhance MET- and EGFR-Driven AKT Signaling in KRAS-Mutant Lung Cancer.
Journal Molecular cancer research : MCR
Vol 14
Issue 10
Date 2016 Oct
URL
Abstract Text Pathway inhibition of the RAS-driven MAPK pathway using small-molecule kinase inhibitors has been a key focus for treating cancers driven by oncogenic RAS, yet significant clinical responses are lacking. Feedback reactivation of ERK driven by drug-induced RAF activity has been suggested as one of the major drug resistance mechanisms, especially in the context of oncogenic RAS. To determine whether additional adaptive resistance mechanisms may coexist, we characterized global phosphoproteomic changes after MEK inhibitor selumetinib (AZD6244) treatment in KRAS-mutant A427 and A549 lung adenocarcinoma cell lines employing mass spectrometry-based phosphoproteomics. We identified 9,075 quantifiable unique phosphosites (corresponding to 3,346 unique phosphoproteins), of which 567 phosphosites were more abundant and 512 phosphosites were less abundant after MEK inhibition. Selumetinib increased phosphorylation of KSR-1, a scaffolding protein required for assembly of MAPK signaling complex, as well as altered phosphorylation of GEF-H1, a novel regulator of KSR-1 and implicated in RAS-driven MAPK activation. Moreover, selumetinib reduced inhibitory serine phosphorylation of MET at Ser985 and potentiated HGF- and EGF-induced AKT phosphorylation. These results were recapitulated by pan-RAF (LY3009120), MEK (GDC0623), and ERK (SCH772984) inhibitors, which are currently under early-phase clinical development against RAS-mutant cancers. Our results highlight the unique adaptive changes in MAPK scaffolding proteins (KSR-1, GEF-H1) and in RTK signaling, leading to enhanced PI3K-AKT signaling when the MAPK pathway is inhibited.This study highlights the unique adaptive changes in MAPK scaffolding proteins (KSR-1, GEF-H1) and in RTK signaling, leading to enhanced PI3K/AKT signaling when the MAPK pathway is inhibited. Mol Cancer Res; 14(10); 1019-29. ©2016 AACR.

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 Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
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 G13C lung adenocarcinoma decreased response Selumetinib Preclinical - Cell culture Actionable In a preclinical study, Selumetinib (AZD6244) only moderately inhibited survival of lung adenocarcinoma cells harboring KRAS G13C mutation due to the adaptive activation of Met, Egfr, and Akt signaling in cells (PMID: 27422710). 27422710
KRAS G12V lung adenocarcinoma decreased response Binimetinib Preclinical - Cell culture Actionable In a preclinical study, Binimetinib (MEK162) only moderately inhibited survival of lung adenocarcinoma cells harboring KRAS G12V mutation due to the adaptive activation of Met, Egfr, and Akt signaling in cells (PMID: 27422710). 27422710
KRAS G12C lung adenocarcinoma decreased response Binimetinib Preclinical - Cell culture Actionable In a preclinical study, Binimetinib (MEK162) only moderately inhibited survival of lung adenocarcinoma cells harboring KRAS G12C mutation due to the adaptive activation of Met, Egfr, and Akt signaling in cells (PMID: 27422710). 27422710
KRAS Q61K lung adenocarcinoma decreased response Selumetinib Preclinical - Cell culture Actionable In a preclinical study, Selumetinib (AZD6244) only moderately inhibited survival of lung adenocarcinoma cells harboring KRAS Q61K mutation due to the adaptive activation of Met, Egfr, and Akt signaling in cells (PMID: 27422710). 27422710
KRAS G13C lung adenocarcinoma decreased response Binimetinib Preclinical - Cell culture Actionable In a preclinical study, Binimetinib (MEK162) only moderately inhibited survival of lung adenocarcinoma cells harboring KRAS G13C mutation due to the adaptive activation of Met, Egfr, and Akt signaling in cells (PMID: 27422710). 27422710
KRAS G12V lung adenocarcinoma decreased response Selumetinib Preclinical - Cell culture Actionable In a preclinical study, Selumetinib (AZD6244) only moderately inhibited survival of lung adenocarcinoma cells harboring KRAS G12V mutation due to the adaptive activation of Met, Egfr, and Akt signaling in cells (PMID: 27422710). 27422710
KRAS Q61K lung adenocarcinoma decreased response Binimetinib Preclinical - Cell culture Actionable In a preclinical study, Binimetinib (MEK162) only moderately inhibited survival of lung adenocarcinoma cells harboring KRAS Q61K mutation due to the adaptive activation of Met, Egfr, and Akt signaling in cells (PMID: 27422710). 27422710
KRAS Q61H lung adenocarcinoma decreased response Binimetinib Preclinical - Cell culture Actionable In a preclinical study, Binimetinib (MEK162) only moderately inhibited survival of lung adenocarcinoma cells harboring KRAS Q61H mutation due to the adaptive activation of Met, Egfr, and Akt signaling in cells (PMID: 27422710). 27422710
KRAS G12R lung adenocarcinoma decreased response Binimetinib Preclinical - Cell culture Actionable In a preclinical study, Binimetinib (MEK162) only moderately inhibited survival of lung adenocarcinoma cells harboring KRAS G12R mutation due to the adaptive activation of Met, Egfr, and Akt signaling in cells (PMID: 27422710). 27422710
KRAS G12R lung adenocarcinoma decreased response Selumetinib Preclinical - Cell culture Actionable In a preclinical study, Selumetinib (AZD6244) only moderately inhibited survival of lung adenocarcinoma cells harboring KRAS G12R mutation due to the adaptive activation of Met, Egfr, and Akt signaling in cells (PMID: 27422710). 27422710
KRAS Q61H lung adenocarcinoma decreased response Selumetinib Preclinical - Cell culture Actionable In a preclinical study, Selumetinib (AZD6244) only moderately inhibited survival of lung adenocarcinoma cells harboring KRAS Q61H mutation due to the adaptive activation of Met, Egfr, and Akt signaling in cells (PMID: 27422710). 27422710
KRAS G12S lung adenocarcinoma decreased response Selumetinib Preclinical - Cell culture Actionable In a preclinical study, Selumetinib (AZD6244) only moderately inhibited survival of lung adenocarcinoma cells harboring KRAS G12S mutation due to the adaptive activation of Met, Egfr, and Akt signaling in cells (PMID: 27422710). 27422710
KRAS mutant lung adenocarcinoma decreased response Selumetinib Preclinical - Cell culture Actionable In a preclinical study, Selumetinib (AZD6244) only moderately inhibited survival of lung adenocarcinoma cells harboring KRAS mutations due to the adaptive activation of Met, Egfr, and Akt signaling in cells (PMID: 27422710). 27422710
KRAS mutant lung adenocarcinoma decreased response Binimetinib Preclinical - Cell culture Actionable In a preclinical study, Binimetinib (MEK162) only moderately inhibited survival of lung adenocarcinoma cells harboring KRAS mutations due to the adaptive activation of Met, Egfr, and Akt signaling in cells (PMID: 27422710). 27422710
KRAS G12S lung adenocarcinoma decreased response Binimetinib Preclinical - Cell culture Actionable In a preclinical study, Binimetinib (MEK162) only moderately inhibited survival of lung adenocarcinoma cells harboring KRAS G12S mutation due to the adaptive activation of Met, Egfr, and Akt signaling in cells (PMID: 27422710). 27422710
KRAS G12C lung adenocarcinoma decreased response Selumetinib Preclinical - Cell culture Actionable In a preclinical study, Selumetinib (AZD6244) only moderately inhibited survival of lung adenocarcinoma cells harboring KRAS G12C mutation due to the adaptive activation of Met, Egfr, and Akt signaling in cells (PMID: 27422710). 27422710