4.5 Article

Neratinib kills B-RAF V600E melanoma via ROS-dependent autophagosome formation and death receptor signaling

Journal

PIGMENT CELL & MELANOMA RESEARCH
Volume 35, Issue 1, Pages 66-77

Publisher

WILEY
DOI: 10.1111/pcmr.13014

Keywords

autophagy; B-RAF; CD95; endoplasmic reticulum (ER) stress; HDAC inhibitor; neratinib

Funding

  1. Massey Cancer Center
  2. Universal Inc.
  3. Chair in Signal Transduction Research
  4. Commonwealth Health Research Board (CHRB) of Virginia
  5. Puma Biotechnology

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Melanoma cells expressing mutant B-RAF V600E are sensitive to treatment with neratinib, especially when combined with HDAC inhibitors. Neratinib affects signaling pathways such as ATM, AMPK, ULK1, and PERK, promoting autophagy and reducing expression of toxic proteins.
Melanoma cells expressing mutant B-RAF V600E are susceptible to treatment with the combination of a B-RAF inhibitor and a MEK1/2 inhibitor. We investigated the impact of the ERBB family and MAP4K inhibitor neratinib on the biology of PDX isolates of cutaneous melanoma expressing B-RAF V600E. Neratinib synergized with HDAC inhibitors to kill melanoma cells at their physiologic concentrations. Neratinib activated ATM, AMPK, ULK1, and PERK and inactivated mTORC1/2, ERK1/2, eIF2 alpha, and STAT3. Neratinib increased expression of Beclin1, ATG5, CD95, and FAS-L and decreased levels of multiple toxic BH3 domain proteins, MCL1, BCL-XL, FLIP-s, and ERBB1/2/4. ATG13 S318 phosphorylation and autophagosome formation was dependent upon ATM, and activation of ATM was dependent on reactive oxygen species. Reduced expression of ERBB1/2/4 required autophagosome formation and reduced MCL1/BCL-XL levels required eIF2 alpha phosphorylation. Maximal levels of eIF2 alpha phosphorylation required signaling by ATM-AMPK and autophagosome formation. Knock down of eIF2 alpha, CD95, FAS-L, Beclin1, and ATG5 or over-expression of FLIP-s significantly reduced killing. Combined knock down of Beclin1 and CD95 abolished cell death. Our data demonstrate that PDX melanoma cells expressing B-RAF V600E are susceptible to being killed by neratinib and more so when combined with HDACi.

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