P-S6 potential ‘functional’ biomarker in BRAF-mutant melanoma

Source: Healio.com/HemOnc Today, November 2013

Suppression of the phosphorylation of the protein S6 after the initiation of RAF inhibitor therapy may serve as a functional biomarker to guide the treatment of patients with BRAF-mutant melanoma, according to study results presented at the International Conference on Molecular Targets and Cancer Therapeutics. Ryan Corcoran, MD, PhD, assistant professor at Massachusetts General Hospital Cancer Center and Harvard Medical School, and colleagues found that suppression of phosphorylation of the ribosomal protein S6 (P-S6) indicated suppression of TORC1 activity after treatment with RAF or MEK inhibitors. The reason we think that TORC1 activity and P-S6 are potentially very useful functional biomarkers is that TORC1 represents a key signaling node that integrates signals from a host of critical upstream pathways, including ERK and the MAP kinase pathways, the PI3 kinase pathway, and many others,” Corcoran said during a press conference. “In sensitive melanoma, our model is that TORC1 activity is driven primarily by MAP kinase first, and when you inhibit this pathway, the RAF inhibitor, P-S6, turns off.” Corcoran and colleagues also found that after treatment with vemurafenib (Zelboraf, Hoffmann-La Roche) in insensitive cancers, P-S6 expression was maintained.

“P-S6 may represent a universal indicator of resistance regardless of the actual mechanism of the tumor resistance,” Corcoran said.

Researchers evaluated biopsies from nine patients with BRAF-mutant melanoma before and after RAF inhibitor treatment. Overall, P-S6 suppression after therapy was associated with significantly improved PFS (HR=0.19; 95% CI, 0.01-0.84). Based on these data, Corcoran and colleagues sought to develop a real-time maintenance to assess P-S6 response after the initiation of RAF inhibition therapy. They found that a multiplexed, quantitative immunofluorescence microscopy of serial fine-needle aspiration biopsy provided a minimally invasive approach of rapidly monitoring response to treatment.

“It’s possible that this can not only identify who is likely to respond, but may actually help us understand the mechanism of why the patient might be resistant and guide treatment choices,” Corcoran said. “The development of this technology and utilization of less-invasive means of monitoring signaling pathways … may actually eliminate the need for serial biopsies and could help facilitate the implementation of the use of functional biomarkers in clinical trials.”