A Common Factor Links Mechanisms of Acquired Resistance to Melanoma Treatment

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Inhibition of ER translocation prevented both ERK reactivation and autophagy, suggesting a potential strategy for improving BRAF and MEK inhibition therapy outcomes.
Inhibition of ER translocation prevented both ERK reactivation and autophagy, suggesting a potential strategy for improving BRAF and MEK inhibition therapy outcomes.

Combined BRAF and MEK inhibition (BRAFi + MEKi) is the standard of care for BRAF-mutation–positive melanoma and lung cancer. However, despite high response rates, patients eventually experience acquired tumor resistance.1,2

“The vast majority of patients treated with [a] BRAF and MEK inhibitor combination experience resistance to therapy,” said Ravi Amaravadi, MD, associate professor of medicine at the Hospital of the University of Pennsylvania and coleader, Cancer Therapeutics Program at the Abramson Cancer Center, University of Pennsylvania, Philadelphia.

Established genetic alterations associated with acquired BRAFi + MEKi resistance in melanoma include NRAS mutations, MEK mutations, BRAF amplifications, and BRAF splice variants, Dr Amaravadi told Cancer Therapy Advisor. Extracellular signal-regulated kinase (ERK) reactivation and autophagy are also mechanisms of acquired resistance to BRAFi + MEKi. They were assumed to operate separately.

But a new study by Dr Amaravadi and colleagues suggests that resistance to BRAF and MEK inhibitors is linked to the migration of ERK and other MAPK pathway proteins from the tumor cell cytoplasm to the endoplasmic reticulum (ER), a process known as “ER translocation.”

The team had previously found that ERK reactivation and the activation of autophagy were seen across melanoma cell lines, whether or not they were resistant to therapy — and that the timing of ERK reactivation following targeted therapy coincided with autophagy activation. That led the researchers to suspect that autophagy and ERK reactivation share a common underlying mechanism.

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