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it is noteworthy that chloroquine and other compounds within its class are not specific autophagy blockers and do exhibit known off target effects. Much effort is currently devoted to the development of autophagy specific inhibitors, when available, future studies evaluating the anti MPNST effects of these novel compounds in combination with Lapatinib PI3K/mTOR inhibitors might be warranted. Inhibition of mTOR signaling by rapamycin has been demonstrated to activate ERK1/2 and Akt in various types of cancer cells, which contributes to rapamycin resistance. However, the downstream effect of rapamycin activated ERKs and Akt on survival or death substrate remains unclear. We discovered that treatment of human lung cancer cells with rapamycin in enhanced phosphorylation of Bad at serine 112 and S136 but not S155 in association with activation of ERK1/2 and Akt. A higher level of Bad phosphorylation was observed in rapamycinresistant cells compared to parental rapamycin sensitive cells. Thus, Bad phosphorylation may contribute to rapamycin resistance. Mechanistically, rapamycin promotes Bad accumulation in the cytosol, enhances Bad/14 3 3 interaction and reduces Bad/Bcl XL binding. Rapamycin induced Bad phosphorylation promotes Lymphatic system its ubiquitination and degradation, with a significant reduction of its half life. Inhibition of MEK/ERK by PD98059 or depletion of Akt by RNA interference blocks rapamycin induced Bad phosphorylation at S112 or S136, respectively. Simultaneous blockage of S112 and S136 phosphorylation of Bad by PD98059 and silencing of Akt significantly enhances rapamycin induced growth inhibition in vitro and synergistically increases the anti tumor efficacy of rapamycin in lung cancer xenografts. Intriguingly, either suppression of Bad phosphorylation at S112 and S136 sites or expression of the non phosphorylatable Bad mutant can reverse rapamycin resistance. These findings uncover a novel mechanism of rapamycin resistance, which may promote the development of new strategies for overcoming rapamycin resistance by manipulating Bad phosphorylation JZL184 at S112 and S136 in human lung cancer. The mammalian target of rapamycin is a serine/threonine kinase and functions as a central regulator of cell growth, cell proliferation and survival. mTOR has been identified as a downstream target of the PI3K/Akt survival pathway. The discovery and clinical development of the highly specific and potent mTOR inhibitor rapamycin and its derivatives as anticancer agents has further enhanced our ability to elucidate mTOR biological function. Inhibition of the mTOR pathway has been proposed to represent a promising therapeutic approach for lung cancer. However, it is increasingly recognized that the clinical activity of rapalog as a single agent is insufficient for achieving a broad and robust anticancer effect. The molecular mechanisms underlying resistance of some cancer cells to mTOR inhibition are not fully understood.