Molecular and Cellular Mechanisms of Resistance to mTORC1 Inhibition in the Skin

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 DESCRIPTION (provided by applicant): The era of precision medicine has ushered in a large number of targeted therapeutics, many aimed at inhibiting PI3K/AKT/mTOR signaling, one of the most commonly up-regulated oncogenic signaling pathways in human tumors. However, these inhibitors have had largely disappointing results in early clinical trials. One of the most compelling explanations for the poor performance of these drugs has been the relief of numerous negative feedback pathways that regulate oncogenic signaling circuits. The last decade of work has revealed that down-regulation of PI3K/AKT/mTOR signaling frequently results in loss of feedback inhibition of upstream receptor tyrosine kinase (RTK) signaling, including ErbB receptor signaling. Now, the key challenge is to elucidate the basic molecular and cellular mechanisms by which this works so that rational strategies can be devised to circumvent tumor resistance to these inhibitors. Using novel mouse models that allow specific perturbation of mTORC1 signaling, we demonstrate that mTORC1 plays a critical role in regulating physiologic EGFR levels and cell-cell adhesion in vivo in the murine skin. Here, we propose to use these powerful genetic systems to tease out the interconnected mechanisms by which mTORC1 inhibition leads to paradoxical up- regulation of EGFR signaling and suppression of adherens junction maturation, potentially key events mediating tumor resistance to PI3K/AKT/mTOR inhibitors. Aim 1 will determine how mTORC1 feedback inhibits upstream EGFR levels and signaling by assessing the effects of mTORC1 perturbation on EGFR trafficking and degradation in keratinocytes. Aim 2 will establish how mTORC1 signaling modulates adherens junction maturation by examining the role of EGFR/PI3K/AKT and Rho family GTPase signaling in this process, and identifying the mTORC1-regulated phospho-proteome downstream of junction formation. Finally, Aim 3 will explore how effects of mTORC1 perturbation on EGFR and cell-cell adhesion affect carcinoma progression of established skin papillomas in two-stage carcinogenesis models. Using isogenic and in vivo systems, this work clarify several basic molecular and cellular mechanisms by which epithelial tumors may develop resistance to mTORC1 inhibition.