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Ref Type Journal Article
PMID (25261369)
Authors Hassan B, Akcakanat A, Sangai T, Evans KW, Adkins F, Eterovic AK, Zhao H, Chen K, Chen H, Do KA, Xie SM, Holder AM, Naing A, Mills GB, Meric-Bernstam F
Title Catalytic mTOR inhibitors can overcome intrinsic and acquired resistance to allosteric mTOR inhibitors.
Abstract Text We tested the antitumor efficacy of mTOR catalytic site inhibitor MLN0128 in models with intrinsic or acquired rapamycin-resistance. Cell lines that were intrinsically rapamycin-resistant as well as those that were intrinsically rapamycin-sensitive were sensitive to MLN0128 in vitro. MLN0128 inhibited both mTORC1 and mTORC2 signaling, with more robust inhibition of downstream 4E-BP1 phosphorylation and cap-dependent translation compared to rapamycin in vitro. Rapamycin-sensitive BT474 cell line acquired rapamycin resistance (BT474 RR) with prolonged rapamycin treatment in vitro. This cell line acquired an mTOR mutation (S2035F) in the FKBP12-rapamycin binding domain; mTORC1 signaling was not inhibited by rapalogs but was inhibited by MLN0128. In BT474 RR cells, MLN0128 had significantly higher growth inhibition compared to rapamycin in vitro and in vivo. Our results demonstrate that MLN0128 may be effective in tumors with intrinsic as well as acquired rapalog resistance. mTOR mutations are a mechanism of acquired resistance in vitro; the clinical relevance of this observation needs to be further evaluated.


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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Sirolimus Sirolimus 20 33
Drug Name Trade Name Synonyms Drug Classes Drug Description
Sirolimus Rapamune Rapamycin mTORC1 Inhibitor 9 Rapamune (sirolimus) binds to the FKBP-12 to generate an immunosuppressive complex that binds and allosterically inhibits mTOR (PMID: 25261369). Rapamune (sirolimus) is FDA approved for the prevention of renal transplant rejection and for patients with lymphangioleiomyomatosis (
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
CDKN2A mut PIK3CA mut breast cancer sensitive Sapanisertib Preclinical Actionable In a preclinical study, a breast cancer cell line harboring mutations in PIK3CA and CDKN2A demonstrated sensitivity to Sapanisertib (MLN0128) in culture (PMID: 25261369). 25261369
PTEN mut TP53 mut skin cancer sensitive Sapanisertib Preclinical Actionable In a preclinical study, a skin cancer cell line harboring mutations in PTEN and TP53 demonstrated sensitivity to Sapanisertib (MLN0128) in culture (PMID: 25261369). 25261369
PTEN mutant breast cancer sensitive Sapanisertib Preclinical Actionable In a preclinical study, Sapanisertib (MLN0128) induced apoptosis and inhibited MTORC1 signaling in breast cancer cells harboring a PTEN mutation (PMID: 25261369). 25261369
PIK3CA mutant Advanced Solid Tumor sensitive Sapanisertib Preclinical Actionable In a preclinical study, human cancer cell lines harboring PIK3CA mutations were sensitive to Sapanisertib (MLN0128) as demonstrated by significant growth inhibition (PMID: 25261369). 25261369