Abstract
Mitogen-activated protein kinase (MAPK) pathway dysregulation is implicated in >30% of all cancers, rationalizing the development of RAF, MEK and ERK inhibitors. While BRAF and MEK inhibitors improve BRAF mutant melanoma patient outcomes, these inhibitors had limited success in other MAPK dysregulated tumors, with insufficient pathway suppression and likely pathway reactivation. In this study we show that inhibition of either MEK or ERK alone only transiently inhibits the MAPK pathway due to feedback reactivation. Simultaneous targeting of both MEK and ERK nodes results in deeper and more durable suppression of MAPK signaling that is not achievable with any dose of single agent, in tumors where feedback reactivation occurs. Strikingly, combined MEK and ERK inhibition is synergistic in RAS mutant models but only additive in BRAF mutant models where the RAF complex is dissociated from RAS and thus feedback productivity is disabled. We discovered that pathway reactivation in RAS mutant models occurs at the level of CRAF with combination treatment resulting in a markedly more active pool of CRAF. However, distinct from single node targeting, combining MEK and ERK inhibitor treatment effectively blocks the downstream signaling as assessed by transcriptional signatures and phospho-p90RSK. Importantly, these data reveal that MAPK pathway inhibitors whose activity is attenuated due to feedback reactivation can be rescued with sufficient inhibition by using a combination of MEK and ERK inhibitors. The MEK and ERK combination significantly suppresses MAPK pathway output and tumor growth in vivo to a greater extent than the maximum tolerated doses of single agents, and results in improved anti-tumor activity in multiple xenografts as well as in two Kras mutant genetically engineered mouse (GEM) models. Collectively, these data demonstrate that combined MEK and ERK inhibition is functionally unique, yielding greater than additive anti-tumor effects and elucidates a highly effective combination strategy in MAPK-dependent cancer, such as KRAS mutant tumors.
Highlights
Oncogenic activation of the RAS-RAF-MEK-ERK (MAPK) pathway through overactive growth factor signaling or oncogenic mutation within the RAS or RAF oncogenes is a central feature in a large number of cancers [1,2,3]
To investigate the concept of dual node targeting of the Mitogen-activated protein kinase (MAPK) pathway with MEK and ERK inhibitors we assessed the FDA-approved MEK inhibitor, cobimetinib [30], and the ERK inhibitor, GDC-0994, a recently developed potent and selective ATP-competitive inhibitor of ERK1/2 [38] (S1a–S1g Fig)
Pathway rectivation was not due to drug instability and replacement of fresh drug-containing media every 24 hr did not alter the outcome. These data demonstrate that KRAS mutant tumor lines respond to MEK or ERK inhibition and that pathway reactivation would be expected to limit the activity of single agent approaches
Summary
Oncogenic activation of the RAS-RAF-MEK-ERK (MAPK) pathway through overactive growth factor signaling or oncogenic mutation within the RAS or RAF oncogenes is a central feature in a large number of cancers [1,2,3]. The duration of response of metastatic melanomas to single-agent BRAF inhibition is limited, largely due to MAPK-pathway reactivation, achieved through multiple means [14]. Combinations of BRAF and MEK inhibitors have been used to induce deeper suppression of MAPK signaling in the BRAF mutant disease setting to preempt MAPK-pathway reactivation and tumor escape. This strategy has been clinically validated with several combinations of BRAF and MEK inhibitors demonstrating meaningful improvements in progression-free survival and patient outcomes in the BRAFV600-mutant metastatic melanoma setting [15,16,17]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
