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|Ref Type||Journal Article|
|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.|
|Date||2016 Mar 08|
|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.|
|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|
|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|
|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|