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MERTK Mediates Intrinsic and Adaptive Resistance to AXL-targeting Agents

Nellie K McDaniel1, Christopher T Cummings2, Mari Iida1

  • 1University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin.

Molecular Cancer Therapeutics
|August 11, 2018
PubMed

Insights

Targeting TAM receptor tyrosine kinases (RTK) AXL and MERTK shows promise for treating aggressive cancers. Dual inhibition of AXL and MERTK overcomes resistance and reduces tumor growth in preclinical models.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Therapeutics

Background:

  • TAM receptor tyrosine kinases (RTK), including TYRO3, AXL, and MERTK, promote tumor growth, survival, and metastasis.
  • AXL and MERTK are overexpressed in aggressive and lethal cancers like head and neck squamous cell carcinoma (HNSCC), triple-negative breast cancer (TNBC), and non-small cell lung cancer (NSCLC).
  • AXL inhibition is being investigated as a therapeutic strategy, but resistance mechanisms need to be understood.

Purpose of the Study:

  • To investigate the efficacy of AXL inhibition alone and in combination with MERTK inhibition in preclinical models of HNSCC, TNBC, and NSCLC.
  • To elucidate the role of MERTK upregulation as a resistance mechanism to AXL-targeting therapies.
  • To evaluate the potential of dual AXL and MERTK targeting for cancer treatment.

Main Methods:

  • Utilized a small-molecule AXL inhibitor, a monoclonal antibody (mAb), and siRNA to inhibit AXL in HNSCC, TNBC, and NSCLC models.
  • Assessed MERTK expression in response to AXL inhibition in cell lines and patient-derived xenografts.
  • Investigated the effects of MERTK inhibition alone and in combination with AXL inhibition.
  • Examined downstream signaling, tumor cell expansion, and tumor growth in vivo.
  • Studied the impact of MERTK overexpression on AXL inhibitor sensitivity.

Main Results:

  • AXL inhibition alone showed limited efficacy in preclinical models, often leading to MERTK upregulation.
  • MERTK inhibition sensitized models to AXL inhibition, suggesting MERTK compensates for AXL blockade.
  • Dual targeting of AXL and MERTK resulted in potent inhibition of downstream signaling and synergistic reduction of tumor cell growth in vitro and in vivo.
  • Ectopic MERTK expression conferred resistance to AXL-targeting strategies.

Conclusions:

  • MERTK upregulation is a key resistance mechanism to AXL inhibition in HNSCC, TNBC, and NSCLC.
  • Combined inhibition of AXL and MERTK offers a more effective therapeutic strategy than targeting AXL alone.
  • Dual targeting of AXL and MERTK holds significant potential for improving patient survival in malignancies where both receptors are expressed.

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