npj Precision Oncology (Dec 2021)

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

  • 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

DOI
https://doi.org/10.1038/s41698-021-00240-w
Journal volume & issue
Vol. 5, no. 1
pp. 1 – 7

Abstract

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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.