Reference Detail

Ref Type

Journal Article

PMID

(26882569)

Authors

Yamaguchi K, Iglesias-Bartolomé R, Wang Z, Callejas-Valera JL, Amornphimoltham P, Molinolo AA, Cohen EE, Califano JA, Lippman SM, Luo J, Gutkind JS

Title

A synthetic-lethality RNAi screen reveals an ERK-mTOR co-targeting pro-apoptotic switch in PIK3CA+ oral cancers.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Oncotarget	7	10	2016 Mar 08	10696-709	Oncotarget

URL

Abstract Text

mTOR inhibition has emerged as a promising strategy for head and neck squamous cell carcinomas (HNSCC) treatment. However, most targeted therapies ultimately develop resistance due to the activation of adaptive survival signaling mechanisms limiting the activity of targeted agents. Thus, co-targeting key adaptive mechanisms may enable more effective cancer cell killing. Here, we performed a synthetic lethality screen using shRNA libraries to identify druggable candidates for combinatorial signal inhibition. We found that the ERK pathway was the most highly represented. Combination of rapamycin with trametinib, a MEK1/2 inhibitor, demonstrated strong synergism in HNSCC-derived cells in vitro and in vivo, including HNSCC cells expressing the HRAS and PIK3CA oncogenes. Interestingly, cleaved caspase-3 was potently induced by the combination therapy in PIK3CA+ cells in vitro and tumor xenografts. Moreover, ectopic expression of PIK3CA mutations into PIK3CA- HNSCC cells sensitized them to the pro-apoptotic activity of the combination therapy. These findings indicate that co-targeting the mTOR/ERK pathways may provide a suitable precision strategy for HNSCC treatment. Moreover, PIK3CA+ HNSCC are particularly prone to undergo apoptosis after mTOR and ERK inhibition, thereby providing a potential biomarker of predictive value for the selection of patients that may benefit from this combination therapy.

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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 Q61L	head and neck squamous cell carcinoma	sensitive	Sirolimus + Trametinib	Preclinical - Cell line xenograft	Actionable	In a preclinical study, Rapamune (sirolimus) worked synergistically with Mekinist (trametinib) to inhibit proliferation of head and neck squamous carcinoma cell lines harboring HRAS Q61L in culture and to reduce tumor growth in cell line xenograft models (PMID: 26882569).	26882569
PIK3CA H1047R	head and neck squamous cell carcinoma	sensitive	Sirolimus + Trametinib	Preclinical - Cell line xenograft	Actionable	In a preclinical study, Rapamune (sirolimus) worked synergistically with Mekinist (trametinib) to inhibit proliferation of head and neck squamous carcinoma cell lines harboring PIK3CA H1047R in culture and to reduce tumor growth in cell line xenograft models (PMID: 26882569).	26882569