Oncology Central

Unsuspected mutations responsible for patient’s dramatic response and resistance to cancer drug

New mechanisms of cancer response and resistance to the drug everolimus has been revealed through the DNA of a woman whose cancer ‘melted away’ for 18 months.

Investigators from Dana-Farber Cancer Institute, the Broad Institute of MIT and Harvard University (all MA, USA) discovered two mutations in the cancer’s DNA that were previously unknown. The first mutation, which accounted for the remarkably long-lasting response to everolimus, made the cancer extraordinarily sensitive to the drug. The second mutation was found 18 months after the treatment had started after it had developed resistance to everolimus. The study is published in The New England Journal of Medicine.

By repeatedly sequencing a patient’s DNA, before treatment and later when the tumor has developed resistance, this single case study shows how unsuspected ‘response’ and ‘resistance’ mutations can be identified that may help guide the treatment of other patients.

“This is personalized, precision medicine at its best,” commented Jochen Lorch, a thyroid cancer specialist at Dana-Farber and senior author of the report. Due to the identification of the mutation that cause the dramatic response to everolimus in a gene termed TSC2, researchers at Dana-Farber will test the effectiveness of the drug in other patients with the mutation in a clinical trial. Studies of patients who are ‘exceptional’ responders are revealing previously unknown response mutations to a variety of drugs and are leading to more of these types of trial, which are known as ‘basket trials’. Patients with a particular mutation are pooled in a basket trial, regardless of the type of cancer they have.

“The study of patients with extraordinary responses can yield critically important insights,” said Nikhil Wagle (Dana-Farber), first author of the report. “These studies could help us develop methods for matching patients to drugs, highlight effective uses for otherwise ‘failed’ therapies, and design new therapeutic strategies to fight cancer.”

Everolimus is approved to treat tumors associated with a rare genetic disorder caused by mutations in the TSC1 and TSC2. Use of the drug is also approved in brain tumors, pancreatic cancer, kidney cancer and advanced breast cancer. The target of everolimus is a protein kinase termed mTOR, which is overactive in some cancers and regulates important cell functions including growth and proliferation.

The stunning response that prompted that search for mutations occurred in a 56-year-old woman diagnosed in 2010 with anaplastic thyroid cancer. Thyroid cancer of this type is nearly always fatal within a few months. “No treatment has ever worked,” continued Lorch. Despite surgery, radiation and chemotherapy, the tumor spread to her lungs.

Lorch decided to include the woman and a handful of other anaplastic patients in a clinical trial of everolimus for a more treatable form of thyroid cancer that he was conducting. After a few months, to his surprise, the tumor shrank to a very small size. The situation remained this way for 18 months, which was previously unheard of, until the tumor began to grow again. The investigators discovered a mutation in the TSC2 gene through the use of whole-exome DNA sequencing, which scans the protein-coding regions of the genome.

mTOR activity is normally suppressed by the TSC2 protein; however, when mTOR is mutated it becomes overactivated, making it a prime target for everolimus.

A mutation in the mTOR protein was revealed in specimens taken from the tumor after it began growing again, one that had not been present in the original sample and prevented everolimus from binding to it. Never before seen in humans, this mutation explained how the cancer developed resistance to the drug.

This was not the end of the story. It was demonstrated by laboratory experiments that the mutated, resistant cancer cells were still sensitive to a different type of mTOR inhibitor. A novel drug of this type is soon to enter clinical trials. Lorch said that the patient described in the case study, who is still alive 4 years after her diagnosis, will receive treatment with this drug.

As the same mechanism of resistance to everolimus may be operating in other cancer types such as breast and kidney cancer, for which the drug is US FDA-approved and frequently used, the case has much broader implications, Lorch added. He said, “Because we could show that an mTOR inhibitor that is using a different mechanism could overcome resistance in anaplastic thyroid cancer, these findings could provide a rationale for treatment once resistance to everolimus occurs.”

Sources: Wagle N, Grabiner BC, Van Allen EM, et al. Response and Acquired Resistance to Everolimus in Anaplastic Thyroid Cancer. New England Journal of Medicine, 2014; 371 (15): 1426–33; Dana- Farber Cancer Institute press release




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