Fig. 3.

A simplified model of the molecular pathways by which pemetrexed, sorafenib, and neratinib combine to kill cancer cells. As a thymidylate synthase inhibitor, pemetrexed causes DNA damage and elevates ZMP levels. ATM phosphorylates the AMPK and ZMP allosterically activates the AMPK which leads to inactivation of mTOR, activation of ULK-1 and ATG13 phosphorylation concomitant with formation of toxic autophagosomes. Sorafenib, in addition to inhibiting RAF kinases and class III RTKs, is an HSP90 family and HSP70 family chaperone inhibitor. Reduced GRP78 function facilitates and endoplasmic reticulum stress response which acts to enhance the levels of Beclin1 and ATG5, facilitating autophagosome formation. The induction of autophagy results in mitochondrial dysfunction which is facilitated by ER stress acting to downregulate MCL-1 and BCL-XL expression. Sorafenib, via inhibition of HSP90 and HSP70, permits AIF, released from the mitochondria, to dissociate from inhibitory chaperones and where it then translocates to the nucleus.