Reference Detail

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.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Oncotarget	5	18	2014 Sep 30	8544-57	Oncotarget

URL

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	21	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 (FDA.gov).

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
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
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
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