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

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 strategi...

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Autores principales:	Niamh Coleman, Vivek Subbiah, Shubham Pant, Keyur Patel, Sinchita Roy-Chowdhuri, Sireesha Yedururi, Amber Johnson, Timothy A. Yap, Jordi Rodon, Kenna Shaw, Funda Meric-Bernstam
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
Acceso en línea:	https://doaj.org/article/627c486cbf7242dbbaee3285ad612a1c
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spelling	oai:doaj.org-article:627c486cbf7242dbbaee3285ad612a1c2021-12-05T12:08:47ZEmergence of mTOR mutation as an acquired resistance mechanism to AKT inhibition, and subsequent response to mTORC1/2 inhibition10.1038/s41698-021-00240-w2397-768Xhttps://doaj.org/article/627c486cbf7242dbbaee3285ad612a1c2021-12-01T00:00:00Zhttps://doi.org/10.1038/s41698-021-00240-whttps://doaj.org/toc/2397-768XAbstract 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.Niamh ColemanVivek SubbiahShubham PantKeyur PatelSinchita Roy-ChowdhuriSireesha YedururiAmber JohnsonTimothy A. YapJordi RodonKenna ShawFunda Meric-BernstamNature PortfolioarticleNeoplasms. Tumors. Oncology. Including cancer and carcinogensRC254-282ENnpj Precision Oncology, Vol 5, Iss 1, Pp 1-7 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
spellingShingle	Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 Niamh Coleman Vivek Subbiah Shubham Pant Keyur Patel Sinchita Roy-Chowdhuri Sireesha Yedururi Amber Johnson Timothy A. Yap Jordi Rodon Kenna Shaw Funda Meric-Bernstam Emergence of mTOR mutation as an acquired resistance mechanism to AKT inhibition, and subsequent response to mTORC1/2 inhibition
description	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.
format	article
author	Niamh Coleman Vivek Subbiah Shubham Pant Keyur Patel Sinchita Roy-Chowdhuri Sireesha Yedururi Amber Johnson Timothy A. Yap Jordi Rodon Kenna Shaw Funda Meric-Bernstam
author_facet	Niamh Coleman Vivek Subbiah Shubham Pant Keyur Patel Sinchita Roy-Chowdhuri Sireesha Yedururi Amber Johnson Timothy A. Yap Jordi Rodon Kenna Shaw Funda Meric-Bernstam
author_sort	Niamh Coleman
title	Emergence of mTOR mutation as an acquired resistance mechanism to AKT inhibition, and subsequent response to mTORC1/2 inhibition
title_short	Emergence of mTOR mutation as an acquired resistance mechanism to AKT inhibition, and subsequent response to mTORC1/2 inhibition
title_full	Emergence of mTOR mutation as an acquired resistance mechanism to AKT inhibition, and subsequent response to mTORC1/2 inhibition
title_fullStr	Emergence of mTOR mutation as an acquired resistance mechanism to AKT inhibition, and subsequent response to mTORC1/2 inhibition
title_full_unstemmed	Emergence of mTOR mutation as an acquired resistance mechanism to AKT inhibition, and subsequent response to mTORC1/2 inhibition
title_sort	emergence of mtor mutation as an acquired resistance mechanism to akt inhibition, and subsequent response to mtorc1/2 inhibition
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/627c486cbf7242dbbaee3285ad612a1c
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Emergence of mTOR mutation as an acquired resistance mechanism to AKT inhibition, and subsequent response to mTORC1/2 inhibition

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