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. 2021 Dec 1;5(1):99.
doi: 10.1038/s41698-021-00240-w.

Emergence of mTOR mutation as an acquired resistance mechanism to AKT inhibition, and subsequent response to mTORC1/2 inhibition

Niamh Coleman  1 , Vivek Subbiah  1 , Shubham Pant  1 , Keyur Patel  2 , Sinchita Roy-Chowdhuri  3 , Sireesha Yedururi  4 , Amber Johnson  2 , Timothy A Yap  1   2 , Jordi Rodon  1 , Kenna Shaw  2 , Funda Meric-Bernstam  5   6   7
Affiliations

Emergence of mTOR mutation as an acquired resistance mechanism to AKT inhibition, and subsequent response to mTORC1/2 inhibition

Niamh Coleman et al. NPJ Precis Oncol. .

Abstract

Acquired resistance to molecular targeted therapy is a significant challenge of the precision medicine era. The ability to understand these mechanisms of resistance may improve patient selection and allow for the development of rationally designed next-line or combination treatment strategies and improved patient outcomes. AKT is a critical effector of the phosphoinositide 3-kinase signaling cascade, one of the most commonly activated pathways in human cancer. Deregulation of signaling pathways, such as RAF/MEK/ERK are previously described mechanisms of resistance to AKT/PI3K inhibitors. Mutations in the mTOR gene, however, are exceedingly rare. We present a case of acquired mTOR resistance, following targeted AKT inhibition, and subsequent response to mTOR1/2 inhibitor in a patient with metastatic endometrial cancer, the first documented response to ATP-competitive mTOR inhibition in this setting. This case supports mTOR mutation as a mechanism of resistance, and underscores the importance of tumor molecular profiling, exemplifying precision medicine in action.

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Conflict of interest statement

The Precision Oncology Decision Support (PODS) team at MD Anderson Cancer Center is receiving funding and technology support from Royal Philips. N.C., K.P., S.R-C., S.Y., A.J., and K.S. report no conflicts of interest. V.S. reports receiving Research funding/Grant support for clinical trials from Roche/ Genentech, Novartis, Bayer, GlaxoSmithKline, Nanocarrier, Vegenics, Celgene, Northwest Biotherapeutics, Berghealth, Incyte, Fujifilm, Pharmamar, D3, Pfizer, Multivir, Amgen, Abbvie, Alfa-sigma, Agensys, Boston Biomedical, Idera Pharma, Inhibrx, Exelixis, Blueprint medicines, Loxo oncology, Medimmune, Altum, Dragonfly Therapeutics, Takeda, and National Comprehensive Cancer Network, NCI-CTEP and UT MD Anderson Cancer Center, Turning point therapeutics, Boston Pharmaceuticals; Travel support from Novartis, Pharmamar, ASCO, ESMO, Helsinn, Incyte and has served on Consultancy/Advisory boards for Helsinn, LOXO Oncology/Eli Lilly, R-Pharma US, INCYTE, QED pharma, Medimmune, Novartis, Relay Therapeutics, Roche; Other: Medscape. S.P. reports receiving Research/Grant Funding through the institution from the following sources: AbbVie, Argule, Bristol-Myers Squibb, Eli Lilly, Five Prime Therapeutics, Glaxo Smith Kline, Holy Stone Healthcare Co., InnoPharmax Inc., Ipsen, Mirati Therapeutics, Inc., Novartis, Onco Response, Parexel International LLC, Red Hill Biopharma Ltd., Rgenix, Sanofi US Services Inc., Sanofi-Aventis, Xencor and Financial Relationship/Speakers Bureau Consultancy from Tyme Inc. and 4D-Pharma. T.Y. reports receiving research support (to institution) from Artios, AstraZeneca, Bayer, Clovis, Constellation, Cyteir, Eli Lilly, EMD Serono, Forbius, F-Star, GlaxoSmithKline, Genentech, ImmuneSensor, Ipsen, Jounce, Karyopharm, Kyowa, Merck, Novartis, Pfizer, Ribon Therapeutics, Regeneron, Repare, Sanofi, Scholar Rock, Seattle Genetics, Tesaro, and Vertex Pharmaceuticals and consultancies from Almac, Aduro, AstraZeneca, Atrin, Axiom, Bayer, Bristol Myers Squibb, Calithera, Clovis, Cybrexa, EMD Serono, F-Star, Guidepoint, Ignyta, I-Mab, Jansen, Merck, Pfizer, Repare, Roche, Rubius, Schrodinger, Seattle Genetics, Varian and Zai Labs. J.R. reports non financial support and reasonable reimbursement for travel from European Journal of Cancer, Vall d’Hebron Institut of Oncology, Chinese University of Hong Kong, SOLTI, Elsevier, GLAXOSMITHKLINE,; receiving consulting and travel fees from Novartis, Eli Lilly, Orion Pharmaceuticals, Servier Pharmaceuticals, Peptomyc, Merck Sharp & Dohme, Kelun Pharmaceutical/Klus Pharma, Spectrum Pharmaceuticals Inc, Pfizer, Roche Pharmaceuticals, Ellipses Pharma, NovellusDx, Ionctura and Molecular Partners (including serving on the scientific advisory board from 2015-present), receiving research funding from Blueprint Pharmaceuticals, Bayer and Novartis, and serving as investigator in clinical trials with Spectrum Pharmaceuticals, Tocagen, Symphogen, BioAtla, Pfizer, GenMab, CytomX, KELUN-BIOTECH, Takeda-Millenium, GLAXOSMITHKLINE, IPSEN and travel fees from ESMO, US Department of Defense, Louissiana State University, Hunstman Cancer Institute, Cancer Core Europe, Karolinska Cancer Institute and King Abdullah International Medical Research Center (KAIMRC), Molecular Partners. F.M-B. reports Consulting from AbbVie, Aduro BioTech Inc., Alkermes, AstraZeneca, DebioPharm, eFFECTOR Therapeutics, F. Hoffman-La Roche Ltd., Genentech Inc., IBM Watson, Infinity Pharmaceuticals, Jackson Laboratory, Kolon Life Science, OrigiMed, PACT Pharma, Parexel International, Pfizer Inc., Samsung Bioepis, Seattle Genetics Inc., Tyra Biosciences, Xencor, Zymeworks. Advisory Committee from Black Diamond, Eisai, Immunomedics, Inflection Biosciences, Karyopharm Therapeutics, Mersana Therapeutics, Puma Biotechnology Inc., Seattle Genetics, Silverback Therapeutics, Spectrum Pharmaceuticals, Zentalis. Sponsored Research from Aileron Therapeutics, Inc. AstraZeneca, Bayer Healthcare Pharmaceutical, Calithera Biosciences Inc., Curis Inc., CytomX Therapeutics Inc., Daiichi Sankyo Co. Ltd., Debiopharm International, eFFECTOR Therapeutics, Genentech Inc., Guardant Health Inc., Klus Pharma, Takeda Pharmaceutical (formerly Millennium Pharmaceutical), Novartis, Puma Biotechnology Inc., Taiho Pharmaceutical Co.Honoraria from Chugai Biopharmaceuticals, Mayo Clinic, Rutgers Cancer Institute of New Jersey. Other (Travel Related) from Beth Israel Deaconess Medical Center.

Figures

Fig. 1
Fig. 1. Treatment timeline.
Timeline summarizing treatment course of the patient, including all systemic treatments that the patient received.
Fig. 2
Fig. 2. Serial axial CT and fused PET/CT images from contrast enhanced PET/CT examinations at baseline, 4.5 months and 8.5 months illustrate disease response.
Serial axial CT (A–C) and fused PET/CT (D–F) images of the abdomen in soft tissue window show response in the mesenteric implant with decreased size (white arrows in A–F) and significantly decreased FDG uptake with a maximum SUV of 10.5 at baseline, 3.6 at 4.5 months follow up and 4.8 at 8.5 months follow up. Serial axial CT (G-I), and fused PET/CT (J-L) images in lung windows showed a response in the lung metastases. The largest metastasis in the lingua remained grossly stable in size (white arrows in G-I) but showed decreased uptake with a maximum SUV of 20.1 at baseline, 8.8 at 4.5 months follow up and 8.6 at 8.5 months follow up. Multiple other smaller lung metastases (black arrows in G-L) also showed decreased size and decreased uptake.
Fig. 3
Fig. 3. Frequency of mTOR mutations.
A Interrogation of IPCT database in MDACC found that of 20,150 patients sequenced, 273 cases of mTOR mutation were identified; cbioportal was used to identify the frequency in other datasets, including Metastatic Solid Cancers (UMich, Nature 2017) and the MSK-IMPACT Clinical Sequencing Cohort (MSKCC, Nat Med 2017),. B Lollipop plot showing the distribution of mTOR mutations, including the mTOR A1459D mutation, detected in this case,.
See this image and copyright information in PMC

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