In their experiments, BRAFi + MEKi treatment-induced ER translocation in melanoma triggered ERK reactivation. That, in turn, increased autophagy.1 Because ER translocation happens so rapidly after BRAFi + MEKi, Dr Amaravadi said he believes the drugs are directly inducing ER translocation.

“Our study involved genetic manipulation of genes to prove the pathway is required for ER translocation,” Dr Amaravadi said. “But in melanoma cells, the components of these pathways are not mutated at the genomic level. The implication of our work is that we found a complex pathway that regulates ER translocation of the MAPK pathway and many steps in this pathway involve druggable enzymes.” 

“We used genetic inhibition of key genes that control ER translocation of the MAPK pathway following BRAF and MEK inhibition to demonstrate that targeting this pathway can enhance the efficacy of BRAF and MEK inhibitors,” including grp78, KSR2, SEC61 and the PERK enzyme, Dr Amaravadi explained. “In each case, the efficacy of BRAF and MEK inhibitor therapy in cell lines was augmented.”

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“Ultimately, ER translocation promotes ERK reactivation, which turns on autophagy through ATF4,” he said. “When ATF4 was inactivated in targeted therapy-resistant, patient-derived xenografts, these tumors suddenly responded to BRAF and MEK inhibition in vivo.”

“Examination of a number of tumor samples from therapy-resistant patients from multiple institutions found that this pathway was almost always activated in the resistance samples, underscoring the point that this resistance mechanism could apply to the vast majority of melanoma patients treated with targeted therapy,” he said.

The research team concluded that “the combination of an ERK inhibitor with BRAFi + MEKi could be effective.” The team is planning to conduct additional studies zeroing in on earlier pathways of ER translocation, Dr Amaravadi said.

References

  1. Ojha R, Leli NM, Onorati A, et al. ER translocation of the MAPK pathway drives therapy resistance in BRAF mutant melanoma [published online December 18, 2018]. Cancer Discov. doi: 10.1158/2159-8290.CD-18-0348
  2. Meierjohann S, Schilling B. BRAF-mutant melanoma: treatment approaches and resistance mechanisms. In: Dammacco F, Silvestris F, eds. Oncogenomics: From Basic Research to Precision Medicine. London, United Kingdom: Academic Press; 2019:669-698.