Priority Research Papers:
A synthetic-lethality RNAi screen reveals an ERK-mTOR co-targeting pro-apoptotic switch in PIK3CA+ oral cancers
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Kosuke Yamaguchi1, Ramiro Iglesias-Bartolomé2, Zhiyong Wang1, Juan Luis Callejas-Valera1, Panomwat Amornphimoltham1, Alfredo A. Molinolo1, Ezra E. Cohen1, Joseph A. Califano1, Scott M. Lippman1, Ji Luo3 and J. Silvio Gutkind1,4
1 Moores Cancer Center, University of California San Diego, San Diego, CA, USA
2 Laboratory of Skin Biology, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, USA
3 Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute (CCR-NCI), National Institutes of Health, Bethesda, MD, USA
4 Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, USA
J. Silvio Gutkind, email:
Keywords: synthetic lethality screen, shRNA library, rapamycin, trametinib, co-targeting therapy
Received: January 15, 2016 Accepted: January 29, 2016 Published: February 13, 2016
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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