Reference Detail

Ref Type Journal Article
PMID (26676756)
Authors Riquelme E, Behrens C, Lin HY, Simon G, Papadimitrakopoulou V, Izzo J, Moran C, Kalhor N, Lee JJ, Minna JD, Wistuba II
Title Modulation of EZH2 Expression by MEK-ERK or PI3K-AKT Signaling in Lung Cancer Is Dictated by Different KRAS Oncogene Mutations.
Journal Cancer research
Vol 76
Issue 3
Date 2016 Feb 01
URL
Abstract Text EZH2 overexpression promotes cancer by increasing histone methylation to silence tumor suppressor genes, but how EZH2 levels become elevated in cancer is not understood. In this study, we investigated the mechanisms by which EZH2 expression is regulated in non-small cell lung carcinoma cells by oncogenic KRAS. In cells harboring KRAS(G12C) and KRAS(G12D) mutations, EZH2 expression was modulated by MEK-ERK and PI3K/AKT signaling, respectively. Accordingly, MEK-ERK depletion decreased EZH2 expression in cells harboring the KRAS(G12C) mutation, whereas PI3K/AKT depletion decreased EZH2 expression, EZH2 phosphorylation, and STAT3 activity in KRAS(G12D)-mutant cell lines. Combined inhibition of EZH2 and MEK-ERK or PI3K/AKT increased the sensitivity of cells with specific KRAS mutations to MEK-ERK and PI3K/AKT-targeted therapies. Our work defines EZH2 as a downstream effector of KRAS signaling and offers a rationale for combining EZH2 inhibitory strategies with MEK-ERK- or PI3K/AKT-targeted therapies to treat lung cancer patients, as stratified into distinct treatment groups based on specific KRAS mutations.

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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
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 G12D EZH2 pos pancreatic cancer no benefit DZNeP + Selumetinib Preclinical - Cell culture Actionable In a preclinical study, the addition of DZNep did not increase sensitivity to Selumetinib (AZD6244) in an EZH2-expressing pancreatic cancer cell line harboring KRAS G12D in culture (PMID: 26676756). 26676756
KRAS G12D EZH2 pos pancreatic cancer sensitive DZNeP + MK2206 Preclinical - Cell culture Actionable In a preclinical study, the addition of DZNep increased sensitivity to MK2206 in an EZH2-expressing pancreatic cancer cell line harboring KRAS G12D in culture (PMID: 26676756). 26676756
KRAS G12C EZH2 pos pancreatic cancer sensitive DZNeP + MK2206 Preclinical - Cell culture Actionable In a preclinical study, the addition of DZNep increased sensitivity to MK2206 in an EZH2-expressing pancreatic cancer cell line harboring KRAS G12C in culture (PMID: 26676756). 26676756
KRAS G12D EZH2 pos lung adenocarcinoma sensitive MK2206 + Tazemetostat Preclinical - Cell culture Actionable In a preclinical study, the addition of Tazemetostat (EPZ-6438) increased sensitivity to MK2206 in an EZH2-expressing lung adenocarcinoma cell line harboring KRAS G12D in culture (PMID: 26676756). 26676756
KRAS G12D EZH2 pos lung adenocarcinoma sensitive DZNeP + MK2206 Preclinical - Cell line xenograft Actionable In a preclinical study, the addition of DZNep increased sensitivity to MK2206 in an EZH2-expressing lung adenocarcinoma cell line harboring KRAS G12D in culture and in xenograft models, resulting in decreased cell survival and tumor growth (PMID: 26676756). 26676756
KRAS G12D EZH2 pos lung adenocarcinoma no benefit GSK343 + Selumetinib Preclinical - Cell culture Actionable In a preclinical study, the addition of GSK343 did not increase sensitivity to Selumetinib (AZD6244) in an EZH2-expressing lung adenocarcinoma cell line harboring KRAS G12D (PMID: 26676756). 26676756
KRAS G12C EZH2 pos lung adenocarcinoma sensitive DZNeP + Selumetinib Preclinical - Cell line xenograft Actionable In a preclinical study, the addition of DZNep increased sensitivity to Selumetinib (AZD6244) in EZH2-expressing lung adenocarcinoma cell lines harboring KRAS G12C, in culture and in xenograft models, resulting in decreased cell survival and tumor growth (PMID: 26676756). 26676756
KRAS G12C EZH2 pos lung adenocarcinoma no benefit GSK343 + MK2206 Preclinical - Cell culture Actionable In a preclinical study, the addition of GSK343 did not increase sensitivity to MK2206 in an EZH2-expressing lung adenocarcinoma cell line harboring KRAS G12C in culture (PMID: 26676756). 26676756
KRAS G12D EZH2 pos colon cancer sensitive DZNeP + MK2206 Preclinical - Cell culture Actionable In a preclinical study, the addition of DZNep increased sensitivity to MK2206 in an EZH2-expressing colon cancer cell line harboring KRAS G12D in culture (PMID: 26676756). 26676756
KRAS G12C EZH2 pos lung adenocarcinoma sensitive GSK343 + Selumetinib Preclinical - Cell culture Actionable In a preclinical study, the addition of GSK343 increased sensitivity to Selumetinib (AZD6244) in EZH2-expressing lung adenocarcinoma cell lines harboring KRAS G12C in culture (PMID: 26676756). 26676756
KRAS G12C EZH2 pos lung adenocarcinoma sensitive Selumetinib + Tazemetostat Preclinical - Cell culture Actionable In a preclinical study, the addition of Tazemetostat (EPZ-6438) increased sensitivity to Selumetinib (AZD6244) in EZH2-expressing lung adenocarcinoma cell lines harboring KRAS G12C in culture (PMID: 26676756). 26676756
KRAS G12D EZH2 pos lung adenocarcinoma no benefit Selumetinib + Tazemetostat Preclinical - Cell culture Actionable In a preclinical study, the addition of Tazemetostat (EPZ-6438) did not increase sensitivity to Selumetinib (AZD6244) in an EZH2-expressing lung adenocarcinoma cell line harboring KRAS G12D (PMID: 26676756). 26676756
KRAS G12D EZH2 pos colon cancer no benefit DZNeP + Selumetinib Preclinical - Cell culture Actionable In a preclinical study, the addition of DZNep did not increase sensitivity to Selumetinib (AZD6244) in an EZH2-expressing colon cancer cell line harboring KRAS G12D in culture (PMID: 26676756). 26676756
KRAS G12D EZH2 pos lung adenocarcinoma no benefit DZNeP + Selumetinib Preclinical - Cell culture Actionable In a preclinical study, the addition of DZNep did not increase sensitivity to Selumetinib (AZD6244) in an EZH2-expressing lung adenocarcinoma cell line harboring KRAS G12D (PMID: 26676756). 26676756
KRAS G12D EZH2 pos lung adenocarcinoma sensitive GSK343 + MK2206 Preclinical - Cell culture Actionable In a preclinical study, the addition of GSK343 increased sensitivity to MK2206 in an EZH2-expressing lung adenocarcinoma cell line harboring KRAS G12D in culture (PMID: 26676756). 26676756
KRAS G12C EZH2 pos pancreatic cancer sensitive DZNeP + Selumetinib Preclinical - Cell culture Actionable In a preclinical study, the addition of DZNep increased sensitivity to Selumetinib (AZD6244) in an EZH2-expressing pancreatic cancer cell line harboring KRAS G12C in culture (PMID: 26676756). 26676756
KRAS G12C EZH2 pos lung adenocarcinoma no benefit MK2206 + Tazemetostat Preclinical - Cell culture Actionable In a preclinical study, the addition of Tazemetostat (EPZ-6438) did not increase sensitivity to MK2206 in an EZH2-expressing lung adenocarcinoma cell line harboring KRAS G12C in culture (PMID: 26676756). 26676756
KRAS G12V EZH2 pos lung adenocarcinoma no benefit DZNeP + MK2206 Preclinical - Cell culture Actionable In a preclinical study, the addition of DZNep did not increase sensitivity to MK2206 in an EZH2-expressing lung adenocarcinoma cell line harboring KRAS G12V (PMID: 26676756). 26676756
KRAS G12V EZH2 pos lung adenocarcinoma no benefit DZNeP + Selumetinib Preclinical - Cell culture Actionable In a preclinical study, the addition of DZNep did not increase sensitivity to Selumetinib (AZD6244) in an EZH2-expressing lung adenocarcinoma cell line harboring KRAS G12V (PMID: 26676756). 26676756
KRAS G12C EZH2 pos lung adenocarcinoma no benefit DZNeP + MK2206 Preclinical - Cell culture Actionable In a preclinical study, the addition of DZNep did not increase sensitivity to MK2206 in an EZH2-expressing lung adenocarcinoma cell line harboring KRAS G12C (PMID: 26676756). 26676756
KRAS G12S EZH2 pos lung adenocarcinoma sensitive DZNeP + MK2206 Preclinical - Cell culture Actionable In a preclinical study, the addition of DZNep increased sensitivity to MK2206 in an EZH2-expressing lung adenocarcinoma cell line harboring KRAS G12S in culture (PMID: 26676756) 26676756
KRAS G12S EZH2 pos lung adenocarcinoma sensitive DZNeP + Selumetinib Preclinical - Cell culture Actionable In a preclinical study, the addition of DZNep increased sensitivity to Selumetinib (AZD6244) in an EZH2-expressing lung adenocarcinoma cell line harboring KRAS G12S in culture (PMID: 26676756). 26676756