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

Kosuke Yamaguchi1, Ramiro Iglesias-Bartolomé2, Zhiyong Wang1

  • 1Moores Cancer Center, University of California San Diego, San Diego, CA, USA.

Oncotarget
|February 17, 2016
PubMed

Insights

Combining mTOR and ERK pathway inhibitors shows promise for head and neck squamous cell carcinoma (HNSCC) treatment. This combination therapy, particularly effective in PIK3CA-mutated HNSCC, offers a potential precision strategy for improved patient outcomes.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Therapeutics

Background:

  • Targeted therapies for head and neck squamous cell carcinomas (HNSCC) face resistance due to adaptive survival signaling.
  • Co-targeting key signaling pathways is crucial for overcoming treatment resistance and enhancing cancer cell killing.

Purpose of the Study:

  • To identify druggable targets for combinatorial signal inhibition in HNSCC.
  • To evaluate the efficacy of co-targeting the mTOR and ERK pathways in HNSCC treatment.

Main Methods:

  • Conducted a synthetic lethality screen using shRNA libraries to identify targets for combination therapy.
  • Investigated the synergistic effects of rapamycin (mTOR inhibitor) and trametinib (MEK1/2 inhibitor) in HNSCC cells in vitro and in vivo.
  • Assessed apoptosis induction via cleaved caspase-3 activation and evaluated the role of PIK3CA mutations.

Main Results:

  • The ERK pathway was identified as a highly represented target for combinatorial inhibition.
  • Combination therapy demonstrated significant synergism in HNSCC cells, including those with HRAS and PIK3CA oncogenes.
  • PIK3CA-mutated HNSCC cells showed potent induction of cleaved caspase-3 and were sensitized to the combination therapy's pro-apoptotic effects.

Conclusions:

  • Co-targeting the mTOR and ERK pathways represents a viable precision strategy for HNSCC treatment.
  • PIK3CA mutations may serve as a predictive biomarker for patient selection in response to mTOR and ERK inhibition.
  • This combination therapy holds potential for more effective HNSCC management.
Keywords:
co-targeting therapyrapamycinshRNA librarysynthetic lethality screentrametinib

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