Emerging Therapies to Optimize MAP Kinase Blockade and Intercept Compensatory Signaling

Keith T. Flaherty, MD
BRAF mutant cancers and, to a lesser extent, RAS mutant cancers are considered the most MAP kinase-dependent of tumors. With melanoma being the tumor that most commonly harbors activating mutations in BRAF (50%) and RAS (25%), clinical evidence shows that MEK inhibitors produce similar response rates in either subpopulation (∼20%). BRAF inhibitors, such as vemurafenib and dabrafenib, spare CRAF and even induce activation of wild-type CRAF and BRAF signaling and have a higher therapeutic index in BRAF mutant melanoma than MEK inhibitors. Resistance to BRAF inhibitors readily develops through CRAF. This creates the opportunity to deploy MEK inhibitors with this class of BRAF inhibitors but also highlights the opportunity for RAF inhibitors that inhibit both BRAF and CRAF. The potential for dual BRAF/CRAF inhibitors to have a greater therapeutic index than MEK inhibitors rests, in part, on putative MEK-independent functions of CRAF that have yet to be validated in the therapeutic resistance setting. Reactivation of the MAP kinase pathway remains a dominant theme in patients treated with BRAF and MEK inhibitors, suggesting that there is an increasing role for additional agents targeting this pathway. ERK inhibitors are in late phase I development, produce toxicities similar to MEK inhibitors, and have yet to be established as being uniquely capable of controlling MAP kinase pathway output and overcoming resistance mechanisms that pertain to MEK inhibitors. HSP90 antagonists are receiving renewed attention as a strategy to downregulate expression of mutant BRAF and wild-type BRAF and CRAF in combination with kinase inhibitors. Preclinical data support the potential of this approach. New tools are needed to monitor output of the MAP kinase pathway to understand the state of patients’ tumors through the course of therapy and recognize points at which new agents or alterations in treatment schedule are needed. Single-cell, bulk tumor, and noninvasive imaging strategies are all in development and may facilitate clinical research in this area.