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Fig. 8 | Journal of Experimental & Clinical Cancer Research

Fig. 8

From: Therapeutic potential of combined BRAF/MEK blockade in BRAF-wild type preclinical tumor models

Fig. 8

Working model of intra-pathway feedbacks and BRAF/MEK growth-inhibitory synergism. a In BRAF-wt/KRAS-mut contexts, selective BRAF inhibition induces BRAF-CRAF dimerization, which hyperactivates the MAPK pathway, thus resulting in relative resistance to treatment. In BRAF-wt/KRAS-wt contexts, paradoxical MAPK activation may be sustained by the RAS-dependent upstream signaling of RTKs (in particular EGFR family members). b Upon allosteric MEK inhibition, the MAPK pathway downstream of a mutant KRAS is efficiently shut down; however, MEK inhibition-induced removal of ERK-mediated feedback RTK inhibition may result in incomplete MAPK pathway inhibition or pathway reactivation, again resulting in relative resistance to the drug. c Combined BRAF/MEK inhibition results in efficient pathway blockade and a synergistic effect on cell growth inhibition, particularly downstream of a mutant KRAS; however, as highlighted also in panel b, in KRAS-wt contexts removal of ERK-mediated feedback RTK inhibition may result in RTK-dependent pathway (re)activation, thus resulting in only partial blockade of downstream signaling. d Thus, in KRAS-wt contexts, triple RTK (EGFR family in the specific case discussed here)/BRAF/MEK inhibition is hypothesized to completely prevent paradoxical MAPK activation; functional growth-inhibitory synergism will then vary according to the degree of intrinsic sensitivity/resistance to RTK inhibition

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