New Mechanism of Resistance to Everolimus in Thyroid Cancer

Papillary thyroid carcinoma on elastography (top) and ultrasonography (bottom); source: Wikimedia Commons, Oreo Priest

Researchers have uncovered two previously unknown mutations in thyroid tumors that can either confer sensitivity or resistance to treatment with the mammalian target of rapamycin (mTOR) inhibitor everolimus. The results of the detailed analysis of a single patient were published in the New England Journal of Medicine.

Researchers performed whole-exome sequencing on a sample of the patient’s pretreated tumor, as well as on a sample of the tumor after the patient had an 18-month response and then developed drug resistance to everolimus treatment while on a phase II clinical trial. The patient was only one of seven anaplastic thyroid cancer patients who responded to everolimus on the trial.

Everolimus is approved by the US Food and Drug Administration (FDA) for the treatment of advanced breast cancer, kidney cancer, and pancreatic neuroendocrine tumors; it is currently being investigated for thyroid cancer. One known mechanism of sensitivity to everolimus is an alteration in the mTOR pathway of tumors that results in upregulation of mTOR activity. But, resistance mechanisms to the drug remain unknown.

The mutation that conferred sensitivity to everolimus in this single-patient analysis was identified as a nonsense mutation in the TSC2 gene, which inactivated the gene. TSC2 normally suppresses the activity of mTOR. Inactivation of TSC2 can lead to unchecked mTOR activity, and allows for sensitivity of at least some tumors to everolimus.

“This is personalized, precision medicine at its best,” said study author Jochen Lorch, MD, a thyroid cancer specialist at Dana-Farber Cancer Institute in Boston, in a statement.

Besides being approved for the previously mentioned cancers, everolimus is also approved by the FDA for a rare genetic disorder, tuberous sclerosis complex, which is caused by mutations in TSC1 and TSC2.

Lorch and Nikhil Wagle, MD, also of Dana-Farber Cancer Institute, along with their colleagues, have now started a clinical trial at Dana-Farber to test the effectiveness of everolimus in patients with various cancers that harbor a TSC2 mutation.

The second mutation identified in the resistant tumor was in the mTOR gene and was not present in the original tumor sample before exposure to everolimus. The researchers found that the mutation prevented everolimus from binding the mTOR protein. The resistant tumor still harbored the TSC2 nonsense mutation. This is the first characterization of an mTOR gene mutation that confers resistance to everolimus, according to the study authors.

But, the resistant thyroid tumor cells were sensitive to torin 1, another mTOR inhibitor. According to Lorch, this type of mTOR inhibitor will soon enter clinical trials. The patient whose tumor samples were used in this study will likely be part of one of these trials.

This type of detailed study of a tumor’s genetic evolution prior to and after being exposed to treatment is an effective approach to understanding genetic alterations that confer either sensitivity or resistance to therapies, which will help to better match a cancer patient to the appropriate therapy, said the study authors.

The resistance mechanism to everolimus identified in this current study may also be relevant to other cancer patients who have relapsed after everolimus therapy.