Autophagy Implicated in Vemurafenib Resistance in BRAF-Mutant Thyroid Cancer

October 20, 2015

Preclinical findings suggest that autophagy inhibition might prove useful in overcoming BRAF-mutant thyroid cancers resistant to vemurafenib.

Autophagy inhibition might prove useful in overcoming BRAF-mutant thyroid cancers’ resistance to vemurafenib, according to preclinical findings presented at the 15th International Thyroid Congress (ITC) and 85th Annual Meeting of the American Thyroid Association (ATA) in Lake Buena Vista, Florida.

“Our data demonstrate that inhibition of autophagy augments the anticancer effects of vemurafenib in BRAF-mutant thyroid cell lines,” reported lead study author Weibin Wang, MD, PhD, of the department of surgery, Weill Medical College, at Cornell University in New York. “Autophagy inhibition may be a beneficial strategy to overcome RAF inhibitor (vemurafenib) resistance in thyroid cancer.”

The RAF inhibitor vemurafenib improves survival among patients with BRAF-mutant metastatic melanoma but is “relatively ineffective” with BRAF-mutant thyroid cancer cells, Dr. Wang noted.

“The reason for this disparity remains unclear,” Dr. Wang said. His team hypothesized that tumor cell autophagy might be involved. Autophagy, like apoptosis, is normally a regulated form of cell destruction. Counterintuitively, however, autophagy can sometimes promote tumor cell survival by destroying cellular mediators of apoptosis. It has also been implicated in tumor drug resistance.

“Autophagy is a highly conserved catabolic process that can induce adaptive drug resistance in a variety of cancer types and treatments,” he explained. “We looked to determine if autophagy is active in BRAF-mutant thyroid cancer and whether autophagy inhibition improves the treatment efficacy of vemurafenib.”

The team studied cell proliferation responses to vemurafenib in five thyroid cancer cell lines, and assessed autophagy by Western blot assay and transmission electron microscopy.

“The autophagy inhibitor hydroxychloroquine (HCQ) augmented the antiproliferative effect when combined with vemurafenib in BRAF-mutant thyroid cell lines,” Dr. Wang concluded.