A never-before-seen autophagy mechanism induced by the BRAF inhibitors vemurafenib and dabrafenib explains the resistance that melanoma develops to these BRAF inhibitors, according to new research.

Half of melanoma patients with the BRAF mutation have a positive response to treatment with BRAF inhibitors, but nearly all of those patients develop resistance to the drugs and experience disease progression. Autophagy is a process by which cancer cells recycle essential building blocks to fuel further growth. The authors found that, if you blocked this pathway with the antimalarial drug hydroxychloroquine (HCQ), the BRAF inhibitors were able to do their job better. This preclinical study was published in the Journal of Clinical Investigation (2014; doi:10.1172/JCI70454).

“This study opens the door for combination therapy with BRAF inhibitors and autophagy inhibitors, which haven’t been explored deeply as a therapeutic option for patients whose tumors are resistant,” said corresponding author Ravi K. Amaravadi, MD, of Penn Medicine’s Abramson Cancer Center in Philadelphia, Pennsylvania. “Here, we show that the BRAF inhibitors induce autophagy as a way to escape cell death, which gives us clues on how to interfere with this mechanism of resistance and improve outcomes for these patients.”

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Based on these promising preclinical results, Amaravadi and his team have already launched a clinical trial for patients with advanced BRAF-mutant melanoma to see how well-tolerated HCQ is with the BRAF inhibitor vemurafenib. “So far,” he said, “we are seeing a benefit to patients and low toxicity.”

BRAF inhibitors are a first line of treatment for melanoma patients who harbor the BRAF mutation, which is an abnormal change in a gene that causes some melanoma tumors to grow and spread more aggressively. Although 50% of patients initially respond to the treatment, nearly 100% exhibit disease progression 7 months after treatment, making it imperative to find a way to re-sensitize the tumor to treatment.

Autophagy has emerged as a key pathway that cancer cells use to survive in the face of assault by chemotherapy and radiation, but it had not been investigated as a druggable target.

Using tumor biopsies from BRAF melanoma patients treated with either BRAF inhibitors or with combined BRAF and MEK inhibitors, a recently FDA-approved drug combination to fight the other mechanisms of resistance, the researchers found that tumors resistant to the BRAF inhibitors had increased levels of autophagy compared with baseline tumors. Moreover, the level of therapy-induced autophagy was correlated with lower response rates and shorter progression-free survival times.

The researchers also examined BRAF-mutant melanoma cell lines, and found that BRAF inhibition induced autophagy by way of an endoplasmic reticulum (ER) stress response. The binding of a BRAF mutation to the ER stress gatekeeper GRP78 is a new and unexpected molecular interaction driving resistance, and establishes a new signaling axis that has multiple drug targets, Amaravadi said. Blocking this mechanism with the antimalarial HCQ limited the autophagy and enhanced cancer cell death in mouse models.