The phosphatidylinositol 3 kinase and mammalian target of rapamycin advanced 1 pathways broadcast signals from receptor tyrosine kinases to downstream effector sites metabolic rate, controlling cell growth, survival, and growth. Numerous feedback programs controlling these oncogenic paths have already been described, and could affect the sensitivity of cancers Imatinib structure to kinase inhibitors. Like, inhibition of mTORC1 relieves proteasomal degradation of IRS 1 resulting in feedback up-regulation of IRS 1/PI3K/ AKT, reducing the efficacy of mTORC1 inhibitors as single agents and prompting using combination therapies. PI3K and AKT inhibitors reduce a poor feedback on other RTKs and ERBB receptors leading to partial re activation of MEK/ERK signaling, PI3K/AKT signaling, and other downstream trails, potentially limiting the power of PI3K inhibitors as single agents. Qualified solutions, including the EGFR inhibitors neuroendocrine system erlotinib and gefitinib, are highly effective when cells are addicted, and inhibition of the prospective leads to down-regulation of survival and important growth signaling pathways, specially MEK/ERK and PI3K/AKT. We recently found that treatment with a variety of a MEK inhibitor and a PI3K inhibitor led to significant apoptosis in EGFR pushed cancers, similar to that induced by an EGFR TKI, while treatment with either path inhibitor alone didn’t produce marked cell death. In those studies, treatment with just one agent MEK inhibitor generated increased AKT phosphorylation. Indeed, some other studies have shown that MEK inhibition leads to increased AKT initial, usually leading to reduced efficacy of MEK inhibitors as single agents. However, the molecular mechanisms underlying this feedback Lonafarnib SCH66336 remain unknown. Several systems for MEK feedback regulation of AKT signaling have now been proposed. As an example, ERK mediated serine phosphorylation of the GAB1 adaptor is shown to negatively regulate GAB1 PI3K binding and downstream AKT signaling. MEK inhibition can also down regulate mTORC1 activating PI3K/AKT signaling, minimizing negative feedback on IGFIR/ IRS 1 and signaling. ERK has also been shown to directly control ERBB tyrosine phosphorylation. However, it remains unclear which mechanisms, if any, are dominant in MEK chemical induced activation of AKT signaling in EGFR or HER2 driven cancers. As multiple MEK and BRAF inhibitors, like the very selective allosteric MEK1/2 inhibitor, AZD6244, are now being produced, understanding the signaling feedbacks induced by MEK inhibitors which could eventually impact their utility will end up increasingly important. In this study, we examined the molecular mechanism by which MEK inhibition results in increased AKT phosphorylation in HER2 and EGFR driven cancers.