Genetic changes enable melanoma cells’ resistance to combo therapy

February 2, 2015

Article

Researchers discovered how melanoma becomes resistant to a new drug combo. Read and learn how it works

Researchers have discovered how melanoma becomes resistant to a new drug combo therapy utilizing BRAF+MEK inhibitors in patients after an initial period of tumor shrinkage.

In a two-year study led by Roger Lo, M.D., assistant professor of dermatology at the UCLA Jonsson Comprehensive Cancer Center, the research team took 43 tumor samples from 15 patients before they were prescribed the new BRAF+MEK inhibitor combo drugs and again after they relapsed due to the melanoma developing drug resistance. The participants all had responded positively to the combo therapy at first, but regressed over time.

The tumors biopsied from the patients were subjected to in-depth analysis of the tumors’ genetic material. This provided leads for the investigators to study how melanoma cells grown in Dr. Lo’s laboratory rewired their growth circuitry to avoid the combo inhibitors.

The researchers found that the melanoma cells resist the combo inhibitors by developing highly unusual genetic changes in certain key cancer genes. These changes not only mark the presence of drug resistant melanoma cells but also can lead to potential ways to shut them off.

“The overall take-home message of this study is that highly unusual melanoma variants exist among patients with metastatic melanoma and are capable of expansion in the presence of even two inhibitors that hit the central mitogen-activated protein kinase pathway,” Dr. Lo tells Dermatology Times. “We need to think beyond targeting the MAPK pathway and dosing medications continuously to treat metastatic melanoma. Dermatologists and patients can expect to see more combinations and regimens of treatments anchored on BRAF+MEK inhibitors to be tested for better efficacy.”

The study, published online Jan. 15th in the journal Cancer Cell, was funded by the National Institutes of Health, the Melanoma Research Alliance and Stand Up To Cancer.

Moriceau G, Hugo W, Hong A, et al. Tunable-Combinatorial Mechanisms of Acquired Resistance Limit the Efficacy of BRAF/MEK Cotargeting but Result in Melanoma Drug Addiction. Cancer Cell. 2015;