BRAF-mutated metastatic melanoma can be treated with the U.S. Food and Drug Administration (FDA)-approved drug vemurafenib, an oral therapy that targets the V600E mutation in the BRAF protein. Another BRAF inhibitor, dabrafenib, has been filed with the FDA for treatment of the same patient population. BRAF inhibition results in rapid shrinkage of tumors for the majority of BRAF-mutated melanoma patients. But while treatment with a BRAF inhibitor alone results in tumor shrinkage in the short-term, patients’ tumors begin to grow again, typically 6 to 7 months after starting treatment.
“Most patients who receive BRAF inhibitor therapy undergo massive [shrinkage of their tumor mass] within 1 to 2 months of starting therapy,” says Roger Lo, MD, PhD, an assistant professor of dermatology and molecular and medical pharmacology at the University of California, Los Angeles (UCLA) School of Medicine and a researcher at the Jonsson Cancer Center, also in Los Angeles. “This initial response is most commonly incomplete and the patient is left with a residual tumor volume.”
The cells in this tumor volume are typically dormant—that is, they have stopped growing. But over time, as the tumor is exposed to the BRAF inhibitor treatment, resistance develops and the tumor begins to grow. This growth occurs because the tumor finds a way to get around the BRAF inhibition by acquiring new mutations.
At the American Association for Cancer Research (AACR) annual meeting last week in Washington, DC, Lo presented research on the ways melanoma tumors can bypass BRAF inhibitor therapy. Lo and colleagues are learning about the ways melanomas adapt to BRAF inhibitor therapy by comparing patient tumor samples before and after treatment with the drug. The researchers are also creating cell lines from these tumor samples to conduct experiments, including testing new drug combinations that may prolong resistance development.
One combination approach currently being tested in the clinic is that of a BRAF and MEK inhibitor. Based on phase II trial data, the combination appears to extend the duration of response to a BRAF inhibitor alone (See blog post on evolution from monotherapy to combination therapy). The BRAF and MEK proteins are both part of the same mitogen-activated kinase (MAPK) pathway. BRAF signals and activates the MEK kinase, leading to activation of growth signals in the cell.
By understanding the mutations that melanomas acquire, Lo and colleagues hope to design new combination therapy trials. The major BRAF inhibitor resistance mutations that have been identified so far include increased copies of the V600E BRAF mutant gene, mutations that result in different splice-variants of BRAF, activation of NRAS (another protein in the MAPK pathway), and strongly-activating MEK mutations. There are other mutations in different signaling pathways that do not occur as frequently. Some are in the phosphoinositide 3-kinase (PIK3) pathway, which is involved in cell growth and is mutated in many different types of cancer.
Lo and colleagues have found that cells resistant to vemurafenib have increased activity of the PIK3 pathway, as measured by activation of AKT, a central protein in the pathway. Inhibiting both BRAF and the PI3K pathways in cell lines can lead to a more robust inhibition of both pathways and delay in signaling that promotes growth when cells are treated with a BRAF inhibitor alone.
But Lo has found that the context of the cell matters. The same mutation acts differently depending on the other mutations present in the cell. This genetic context of tumors will affect selection of patients likely to benefit from the various combination therapies being developed, such as combining a BRAF inhibitor with an AKT or PI3K inhibitor. Combining either of these with a BRAF inhibitor, or even a triple-combination therapy, is a rational strategy that may delay resistance development in certain patients with BRAF-mutated melanoma.