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	Vol	Issue	Date	Pages	Journal Short Title
Oncotarget	6	39	2015 Dec 08	42183-96	Oncotarget

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

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
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 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 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 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	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 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 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 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 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 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 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 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	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 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 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 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
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