Reference Detail

Ref Type Journal Article
PMID (26544513)
Authors Kiessling MK, Curioni-Fontecedro A, Samaras P, Atrott K, Cosin-Roger J, Lang S, Scharl M, Rogler G
Title Mutant HRAS as novel target for MEK and mTOR inhibitors.
Journal Oncotarget
Vol 6
Issue 39
Date 2015 Dec 08
URL
Abstract Text HRAS is a frequently mutated oncogene in cancer. However, mutant HRAS as drug target has not been investigated so far. Here, we show that mutant HRAS hyperactivates the RAS and the mTOR pathway in various cancer cell lines including lung, bladder and esophageal cancer. HRAS mutation sensitized toward growth inhibition by the MEK inhibitors AZD6244, MEK162 and PD0325901. Further, we found that MEK inhibitors induce apoptosis in mutant HRAS cell lines but not in cell lines lacking RAS mutations. In addition, knockdown of HRAS by siRNA blocked cell growth in mutant HRAS cell lines. Inhibition of the PI3K pathway alone or in combination with MEK inhibitors did not alter signaling nor had an impact on viability. However, inhibition of mTOR or combined inhibition of MEK and mTOR reduced cell growth in a synergistic manner. Finally, Ba/F3 cells transformed with mutant HRAS isoforms Q61L, Q61R and G12V demonstrated equal sensitivity towards MEK and mTOR inhibition. Our results show that HRAS mutations in cancer activate the RAS and mTOR pathways which might serve as a therapeutic option for patients with HRAS mutant tumors.

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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
HRAS G12V Advanced Solid Tumor sensitive Everolimus Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing HRAS G12V demonstrated sensitivity to growth inhibition by Afinitor (everolimus) in culture (PMID: 26544513). 26544513
HRAS G12V urinary bladder cancer sensitive Everolimus + Selumetinib Preclinical - Cell culture Actionable In a preclinical study, the combination of Selumetinib (AZD6244) and Afinitor (everolimus) reduced phosphorylation of ERK and S6 and worked synergistically to inhibit growth of a bladder cancer cell line harboring HRAS G12V in culture (PMID: 26544513). 26544513
HRAS G12V urinary bladder cancer sensitive Binimetinib + Everolimus Preclinical - Cell culture Actionable In a preclinical study, the combination of Binimetinib (MEK162) and Afinitor (everolimus) reduced phosphorylation of ERK and S6 and worked synergistically to inhibit growth of a bladder cell line harboring HRAS G12V in culture (PMID: 26544513). 26544513
HRAS Q61L Advanced Solid Tumor sensitive Binimetinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing HRAS Q61L demonstrated sensitivity to growth inhibition by Binimetinib (MEK162) in culture (PMID: 26544513). 26544513
HRAS mutant Advanced Solid Tumor predicted - sensitive Binimetinib Preclinical - Cell culture Actionable In a preclinical study, Binimetinib (MEK162) inhibited growth and induced apoptosis in human solid tumor cell lines harboring HRAS mutations in culture (PMID: 26544513). 26544513
HRAS Q61L lung squamous cell carcinoma sensitive Selumetinib Preclinical - Cell line xenograft Actionable In a preclinical study, Selumetinib (AZD6244) inhibited growth of a lung squamous cell carcinoma cell line harboring HRAS Q61L in culture, and inhibited tumor growth in xenograft models (PMID: 26544513). 26544513
HRAS mutant Advanced Solid Tumor predicted - sensitive Everolimus Preclinical - Cell culture Actionable In a preclinical study, human solid tumor cell lines harboring HRAS mutations demonstrated increased sensitivity to growth inhibition by Afinitor (everolimus) in culture compared to cell lines with wild-type HRAS (PMID: 26544513). 26544513
HRAS Q61L lung squamous cell carcinoma sensitive Binimetinib + Everolimus Preclinical - Cell culture Actionable In a preclinical study, the combination of Binimetinib (MEK162) and Afinitor (everolimus) reduced phosphorylation of ERK and S6 and worked synergistically to inhibit growth of a lung squamous cell carcinoma cell line harboring HRAS Q61L in culture (PMID: 26544513). 26544513
HRAS Q61L Advanced Solid Tumor sensitive Binimetinib + Everolimus Preclinical - Cell culture Actionable In a preclinical study, the combination of Binimetinib (MEK162) and Afinitor (everolimus) worked synergistically to inhibit growth of transformed cells expressing HRAS Q61L in culture (PMID: 26544513). 26544513
HRAS Q61R Advanced Solid Tumor sensitive Binimetinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing HRAS Q61R demonstrated sensitivity to growth inhibition by Binimetinib (MEK162) in culture (PMID: 26544513). 26544513
HRAS G12V Advanced Solid Tumor sensitive Binimetinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing HRAS G12V demonstrated sensitivity to growth inhibition by Binimetinib (MEK162) in culture (PMID: 26544513). 26544513
HRAS Q61L lung squamous cell carcinoma sensitive Everolimus + Selumetinib Preclinical - Cell line xenograft Actionable In a preclinical study, the combination of Selumetinib (AZD6244) and Afinitor (everolimus) inhibited growth of a lung squamous cell carcinoma cell line harboring HRAS Q61L in culture, and inhibited tumor growth in xenograft models, with increased efficacy compared to either agent alone (PMID: 26544513). 26544513
HRAS Q61R Advanced Solid Tumor sensitive Everolimus Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing HRAS Q61R demonstrated sensitivity to growth inhibition by Afinitor (everolimus) in culture (PMID: 26544513). 26544513
HRAS Q61L Advanced Solid Tumor sensitive Everolimus Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing HRAS Q61L demonstrated sensitivity to growth inhibition by Afinitor (everolimus) in culture (PMID: 26544513). 26544513
HRAS mutant Advanced Solid Tumor predicted - sensitive Selumetinib Preclinical - Cell culture Actionable In a preclinical study, human solid tumor cell lines harboring HRAS mutations demonstrated increased sensitivity to growth inhibition by Selumetinib (AZD6244) in culture compared to cell lines with wild-type HRAS (PMID: 26544513). 26544513
HRAS G12V Advanced Solid Tumor sensitive Binimetinib + Everolimus Preclinical - Cell culture Actionable In a preclinical study, the combination of Binimetinib (MEK162) and Afinitor (everolimus) worked synergistically to inhibit growth of transformed cells expressing HRAS G12V in culture (PMID: 26544513). 26544513
HRAS Q61L lung squamous cell carcinoma sensitive AZD8055 + Binimetinib Preclinical - Cell culture Actionable In a preclinical study, the combination of Binimetinib (MEK162) and AZD8055 reduced phosphorylation of ERK and S6 and worked synergistically to inhibit growth of a lung squamous cell carcinoma cell line harboring HRAS Q61L in culture (PMID: 26544513). 26544513
HRAS Q61L lung squamous cell carcinoma no benefit Buparlisib Preclinical - Cell culture Actionable In a preclinical study, BKM120 did not inhibit growth of a lung squamous cell carcinoma cell line harboring HRAS Q61L in culture (PMID: 26544513) 26544513