An Acquired MTOR Mutation Confers Resistance to Allosteric mTOR Inhibition

Anaplastic thyroid cancer is an aggressive, lethal cancer with no effective therapies and a median overall survival of 5 months. In a phase 2 study of the allosteric mTOR inhibitor everolimus in patients with thyroid cancer, the only patient with anaplastic thyroid cancer who responded out of seven enrolled in the trial had an exceptional response lasting 18 months, at which time she developed progressive disease. To understand the mechanistic basis for this initial response and subsequent acquired resistance, Wagle and colleagues performed whole-exome sequencing of the pretreatment and everolimus-resistant tumor samples. Consistent with reports of mutations in other tumor types that result in mTOR pathway activation and exquisite sensitivity to mTOR inhibitors, the patient's pretreatment tumor harbored a TSC2 nonsense mutation that led to loss of TSC2 protein and activation of downstream mTOR targets. This mutation persisted in the resistant tumor, but the resistant tumor also contained a somatic MTOR^F2108L mutation. Analysis of the mTOR structure revealed that the F2108 residue lies within the domain where everolimus and other allosteric inhibitors bind and suggested that an F2108L substitution would sterically hinder everolimus binding. Consistent with this possibility, expression of MTOR^F2108L conferred resistance to the allosteric mTOR inhibitor rapamycin but had no effect on sensitivity to torin 1, an ATP-competitive mTOR kinase inhibitor that binds the mTOR active site. Together with previous reports of exceptional responders to mTOR inhibition, the characterization of this patient strongly supports the development of mTOR inhibitor basket trials for patients with mTOR pathway mutations regardless of tumor type. Moreover, the identification of an acquired MTOR mutation that confers resistance to allosteric inhibitors suggests that such patients with resistant mTOR pathway–dependent tumors may respond to mTOR kinase inhibitors.

Wagle N, Grabiner BC, Van Allen EM, Amin-Mansour A, Taylor-Weiner A, Rosenberg M, et al. Response and acquired resistance to everolimus in anaplastic thyroid cancer. N Engl J Med 2014;371:1426–33.