Overcoming Drug Resistance in Melanoma Treatment


Researchers discuss mechanism for overcoming resistance to drugs that target BRAF protein.

Researchers discuss mechanism for overcoming resistance to drugs that target BRAF protein.

Despite improved survival rates from melanoma, many patients still experience a relapse when remaining tumor cells adapt and become resistant to therapy.

In a study published online in the journal Oncogene, researchers from Moffitt Cancer Center found a novel mechanism that causes melanoma cells to become resistant to drugs that target the BRAF protein.

Approximately 50% of melanoma tumors test positive for BRAF gene mutations. Drugs like dabrafenib and vemurafenib were previously approved to treat patients with this mutation, however many patients experience a relapse due to resistance associated with reactivation of the BRAF protein communication pathway in tumor cells.

In addition to BRAF mutations, patients with PTEN mutations also may have a poorer response to dabrafenib and vemurafenib therapy. In an effort to evaluate the mechanism responsible for BRAF inhibitors resistance, it was found that BRAF inhibitors cause BRAF and PTEN mutant melanoma cells to increase levels of the protein fibronectin, which is expressed in the space surrounding cells.

The results showed higher levels of fibronectin permit melanoma cells to form a protective environment that diminishes the ability of BRAF inhibitors to kill tumor cells.

Furthermore, it was found that melanoma patients with PTEN mutations and higher levels of fibronectin in tumors typically have lower overall survival rates. The researchers found that treating tumors with BRAF inhibitors in combination with a drug targeting the tumor protective environment significantly increases the efficacy of the BRAF inhibitor.

"This study gives important new insights into why nearly all melanoma patients fail targeted therapy," said researcher Keiran S. Smalley, PhD, in a press release.

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