Although these compounds lead to stronger inhibition of mTORC1, they also fully suppress mTOR complex 2 (mTORC2), a second physically and functionally distinct mTOR-containing protein complex. 11, 12 Inhibitors targeting the mTOR kinase domain, such as MLN0128, CC-223, and AZD-2014, have been used in many preclinical studies and are currently being tested to treat cancers in Phase I/II clinical trials ( ). 10 The allosteric mTORC1 inhibitor rapamycin (also known as sirolimus or Rapamune) and its analogs (e.g., everolimus, temsirolimus), collectively referred to as rapalogs, are partial inhibitors of mTORC1 and currently the only clinically approved mTORC1 inhibitors for any indication. However, mTORC1 inhibitors have had limited success as single agents. ![]() Owing to the prevalence of mTORC1 activation in tumors, there has been great interest in targeting mTORC1 pharmacologically. 5, 6 TSC1 and TSC2 mutations can also occur in sporadic cancers, with the most common being bladder and liver cancer. ![]() This autosomal dominant disorder is characterized by tumors in multiple organ systems, most frequently affecting the brain, kidney, skin, heart and lung, as well as neurological manifestations, including epilepsy and autism spectrum disorder. The genetic tumor syndrome TSC results from germline or mosaic loss-of-function mutations in TSC1 or TSC2, leading to constitutive activation of mTORC1 in the widespread neoplastic lesions inflicting individuals with TSC. Although TSC1 and TSC2 themselves are tumor suppressors, the TSC complex is often functionally inactivated in cancer through mutations in upstream oncogenes and tumor suppressors, thus providing the most frequent route of mTORC1 activation in cancer. 4 The tuberous sclerosis complex (TSC) protein complex, comprising TSC1, TSC2 and TBC1D7, is an essential negative regulator of mTORC1. 1, 2, 3 The activation of mTORC1 drives growth-promoting anabolic processes, including a coordinated increase in the synthesis of proteins, lipids and nucleotides. The mechanistic target of rapamycin (mTOR) complex 1 (mTORC1) is a critical convergence point for the most common oncogenic signals, leading to aberrant, growth factor-independent activation of mTORC1 signaling in the majority of human cancers. These data expose a therapeutic vulnerability in regulation of the apoptotic machinery downstream of mTORC1 that promotes a cytotoxic response to rapamycin. The BCL-2/BCL-X L inhibitor ABT-263 synergizes with rapamycin to induce apoptosis in TSC-deficient cells and in a mouse tumor model of TSC, resulting in a more complete and durable response. In TSC2-deficient cells and tumors, we find that mTORC1 inhibitors shift cellular dependence from MCL-1 to BCL-2 and BCL-X L for survival, thereby altering susceptibility to BH3 mimetics that target specific pro-survival BCL-2 proteins. We sought to determine the effects of mTORC1 on the core regulators of intrinsic apoptosis. Clinically approved mTORC1 inhibitors, such as rapamycin, elicit a cytostatic effect that fails to eliminate tumors and is rapidly reversible. MTORC1 is aberrantly activated in cancer and in the genetic tumor syndrome tuberous sclerosis complex (TSC), which is caused by loss-of-function mutations in the TSC complex, a negative regulator of mTORC1.
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