Keith Flaherty, MD
While BRAF inhibitors have significantly enhanced melanoma treatment, there is still room for advancement. However, making real strides in devising treatments that provide durable tumor control will require an understanding of BRAF resistance mechanisms, according to Keith Flaherty, MD, associate professor of Medicine at Harvard Medical School and director of Developmental Therapeutics at the Massachusetts General Hospital Cancer Center.
“With BRAF monotherapies and combination therapies, we can extend survival in some patients,” Flaherty said in presentation at the 2015 Society for Melanoma Research Congress. “Enhancing patient outcomes also requires understanding the unique genetic wiring in tumors that [do and] do not manifest resistance,” he said.
Scientists have now accumulated 5 to 6 years of follow-up data on melanoma patients treated with BRAF inhibitor therapies. “We know that melanoma is not uniformly complex. And there’s quite a lot of genetic heterogeneity in terms of amplification and deletion events, and number of mutations in melanoma tumors,” Flaherty said.
Flaherty and colleagues have now performed whole genome sequencing on a large cohort of patients who have undergone BRAF inhibitor therapy. “We’re now moving toward correlating genetic differences with clinical outcomes,” he said.
Right now scientists are attempting to learn the mechanisms of resistance from static biomarkers before deploying patients to therapy. It is important that scientists learn to understand the baseline features of tumors and adaptations of tumors during therapy that make them resistant. With this understanding, patients likely to develop resistance can receive more aggressive treatments, Flaherty said.
Scientists now know that the reengagement of the map kinase signaling pathway plays a part in melanoma treatment resistance, including resistance to BRAF inhibitors. Scientists need to develop therapies that can reengage with the map kinase pathway to try to squelch the mechanisms of reactivation, which can make patients resistant even to combination therapies, Flaherty said. Other baseline tumor features, however, may also play a part in resistance.
MITF expression, which is correlated with BCL2A1 expression, is another potential mechanism for the development of resistance, Flaherty noted. In genetic studies on melanoma tumors, those patients who had upregulated BCL2A1 were more likely to have blunted response to BRAF inhibitor therapy, he added.
Patients low in MITF expression, who also are low in the AXL protein coding gene are also more likely to develop resistance. “Patients with low MITF expression with low AXL expression have been shown to have the shortest duration of tumor control,” Flaherty said.
The challenge is to triage patients early in the course of therapy based on the likelihood that their tumors will be resistant. These harder-to-treat patients could then should be treated with doublet therapy, or by adding a MTOR inhibitor or JAK inhibitor to treatment. Both these approaches have shown potential in patient treatment and in the laboratory for overcoming BRAF inhibitor therapy resistance, Flaherty said.
The issue of whether such genetic changes in a tumor could be assessed prior to or during initial therapy has not yet been fully resolved, Flaherty noted. “As we learn more about the genetic mechanisms of resistance, it makes sense to biopsy patient tumors to assess and measure resistance.”
“Another question is what drives persistence after maximal response to BRAF inhibitor therapy. And that’s more difficult to assess in treated patients,” Flaherty said. “In patients who have deep responses to therapy, their metastases are gone in weeks. So biopsies of these tumors are a challenge.”
Eventually, researchers hope to develop blood-based biomarkers that could be correlated with genetic changes in tumors that drive resistance, Flaherty noted. Even if the genetics of resistance are not hardwired, assessing baseline tumor biomarkers will eventually play a part in selecting the best therapeutic approach for each patient, Flaherty said.