Combating Resistance Mechanisms to Treatment in Thyroid Cancer


Lova Sun, MD, MSCE, discusses resistance mechanisms against targeted agents for the treatment of thyroid cancer.

While targeted therapies for thyroid cancer can be very effective, they aren't a permanent solution. Patients eventually develop resistance, rendering the drugs ineffective. Researchers are actively studying these resistance mechanisms, which can involve mutations that prevent the drug from binding or activation of alternative pathways.

Identifying these resistance mechanisms is crucial. When resistance occurs, doctors can look for other genetic mutations that might be targeted by other existing drugs. Additionally, next-generation drugs like repotrectinib (Augtyro) and selitrectinib are showing promise in clinical trials for patients who no longer respond to first-line therapies.

Biopsies of the progression site can also be informative, potentially revealing additional treatment options. While not always successful, this approach offers hope for continued therapy even after initial resistance develops.

Here, Lova Sun, MD, MSCE, discusses resistance mechanisms against targeted agents for the treatment of thyroid cancer.


0:05 | It is important to keep in mind that even though these drugs that I just talked about work well, they are not curative, and they do not work forever. Generally, we have responses that last for many months or even years on these agents, but eventually, patients do progress, and we are learning more about the mechanisms of resistance. When these patients do start not to respond to these agents.

0:35 | Those are things like solvent front and gatekeeper mutations that prevent the drug from binding in the way they used to, as well as off-target resistance that we can see in genes such as MET, KRAS, and even BRAF that can sometimes be targeted with other drugs that are approved. It highlights the importance of looking for resistance mechanisms. At the time of progression on these agents, there are trials of next-generation agents such as repotrectinib and selitrectinib that have some efficacy, even after progression on the approved agents that. We will await data from [these agents] and [see if they] are worth looking into if they are available for our patients. [Also,] biopsy, seeing a site of progression, can sometimes, though not always, lend an additional therapeutic option.

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