Biomolecules & Therapeutics

The Korean Society of Applied Pharmacology (한국응용약물학회)
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Differential Sensitivity of Wild-Type and BRAF-Mutated Cells to Combined BRAF and Autophagy Inhibition

  • Yeom, Hojin (Division of Life Sciences, College of Life Sciences and Bioengineering, Incheon National University) ;
  • Hwang, Sung-Hee (Division of Life Sciences, College of Life Sciences and Bioengineering, Incheon National University) ;
  • Han, Byeal-I (Institute for New Drug Development, Incheon National University) ;
  • Lee, Michael (Division of Life Sciences, College of Life Sciences and Bioengineering, Incheon National University)
  • Received : 2020.11.09
  • Accepted : 2021.01.19
  • Published : 2021.07.01
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Abstract

BRAF inhibitors are insufficient monotherapies for BRAF-mutated cancer; therefore, we investigated which inhibitory pathway would yield the most effective therapeutic approach when targeted in combination with BRAF inhibition. The oncogenic BRAF inhibitor, PLX4720, increased basal autophagic flux in BRAF-mutated cells compared to wild-type (WT) BRAF cells. Interestingly, early autophagy inhibition improved the effectiveness of PLX4720 regardless of BRAF mutation, whereas late autophagy inhibition did not. Although ATG5 knockout led to PLX4720 resistance in both WT and BRAF-mutated cells, the MEK inhibitor trametinib exhibited a synergistic effect on PLX4720 sensitivity in WT BRAF cells but not in BRAF-mutated cells. Conversely, the prolonged inhibition of endoplasmic reticulum (ER) stress reduced basal autophagy in BRAF-mutated cells, thereby increasing PLX4720 sensitivity. Taken together, our results suggest that the combined inhibition of ER stress and BRAF may simultaneously suppress both pro-survival ER stress and autophagy, and may therefore be suitable for treatment of BRAF-mutated tumors whose autophagy is increased by chronic ER stress. Similarly, for WT BRAF tumors, therapies targeting MEK signaling may be a more effective treatment strategy. Together, this study presents a rational combination treatment strategy to improve the efficacy of BRAF inhibitors depending on BRAF mutation status.

Keywords

Acknowledgement

This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Ministry of Science and ICT (MIST) (NRF-2019R1F1A1048733) and by the Incheon National University Research Grant in 2019.

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