“…Although inhibitor-modulated CA has been recognized as a possible contributor to the entire PA phenomenon ( Heidorn et al, 2010 ; Jin et al, 2017 ), it has been underappreciated as a mechanism capable of driving PA. Supporting this assertion is that CA has neither been discussed as a motivation for the development of third-generation RAF inhibitors ( Nakamura et al, 2013 ; Peng et al, 2015 ; Zhang et al, 2015 ) nor has it been included in recent mathematical analyses of PA and of RAF signaling ( Fröhlich et al, 2022 ; Kholodenko, 2015 ; Rukhlenko et al, 2018 ; Varga et al, 2017 ). This is notable as both drug development and mathematical analyses pay considerable attention to conformations within the kinase domain (i.e., whether the alpha-C helix and DFG motif are in the ‘in’ or ‘out’ conformations) ( Kholodenko, 2015 ; Nakamura et al, 2013 ; Peng et al, 2015 ; Rukhlenko et al, 2018 ; Zhang et al, 2015 ).…”