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Looking for Driver Pathways of Acquired Resistance to Targeted Therapy: Drug Resistant Subclone Generation and Sensitivity Restoring by Gene Knock-down
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ER Translocation of the MAPK Pathway Drives Therapy Resistance in BRAF-Mutant Melanoma

Rani Ojha1, Nektaria M Leli2, Angelique Onorati1

  • 1Abramson Cancer Center and Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.

Cancer Discovery
|December 20, 2018
PubMed

Insights

BRAF and MEK inhibitors induce endoplasmic reticulum translocation of the MAPK pathway, causing ERK reactivation and autophagy. Targeting this mechanism could overcome resistance to BRAF + MEK inhibitors (BRAFi + MEKi) in BRAF-mutant cancers.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Therapy

Background:

  • Resistance to BRAF and MEK inhibitors (BRAFi + MEKi) in BRAF-mutant tumors is a significant clinical challenge.
  • Mechanisms of resistance, including ERK reactivation and autophagy, are not fully understood.
  • The interplay between these resistance pathways and their induction by BRAFi + MEKi requires elucidation.

Purpose of the Study:

  • To investigate the mechanism by which BRAFi + MEKi induce ERK reactivation and autophagy in BRAF-mutant melanoma.
  • To identify novel druggable targets for overcoming resistance to BRAFi + MEKi therapy.

Main Methods:

  • Utilized BRAF-mutant melanoma cell lines and patient-derived xenografts.
  • Investigated the role of endoplasmic reticulum (ER) translocation of the MAPK pathway.
  • Assessed the impact of inhibiting ER translocation on ERK reactivation, autophagy, and therapeutic response.
  • Analyzed patient tumor samples for biomarkers of resistance.

Main Results:

  • BRAFi + MEKi induced SEC61-dependent ER translocation of the MAPK pathway via GRP78 and KSR2.
  • Inhibition of ER translocation prevented ERK reactivation and subsequent autophagy.
  • Reactivated ERK phosphorylated ATF4, leading to cytoprotective autophagy.
  • Upregulation of GRP78 and ATF4 phosphorylation were observed in resistant patient tumors and xenografts.

Conclusions:

  • BRAFi + MEKi induce a novel ER translocation mechanism of the MAPK pathway, driving ERK reactivation and autophagy.
  • This ER translocation is a critical driver of targeted therapy resistance.
  • Targeting this pathway, including GRP78, KSR2, or ATF4, presents a promising strategy to enhance BRAFi + MEKi efficacy.

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