NTRK: An Attractive Target for Therapy

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Transcript:

David Hyman, MD: One of the features of NTRK that’s made it an attractive and a good target for cancer therapy is that after we develop as embryos, there’s very limited role for TRK proteins in children and adults. That role is really limited to helping us balance and position our bodies in space and it also plays a little bit of a role in sensing pain and satiation when eating. But these roles are really limited to the function of TRK in our brains, and especially when we don’t achieve high levels of TRK inhibitors in the brain, we’re able to mitigate most or all of these adverse effects in patients.

The role of NTRK in cancer really occurs when the NTRK gene becomes abnormally stuck or fused to another gene and that leads to overexpression of this new fusion, this TRK fusion in cancer. And that leads this cancer cell to grow uncontrollably and become addicted to the presence of this TRK fusion.

In solid tumors, we see all different classes of genetic alterations in TRK. We can see TRK fusions, we can see mutations, or gene amplifications. As far as we know, the only class of alteration that’s therapeutically actionable are fusions. We haven’t been able to demonstrate that mutations or amplifications of the NTRK genes lead to oncogene addiction or the ability to target them in the clinic. So the focus consequently of TRK inhibitor development has really been just in NTRK fusions.

It’s been a little hard to have a firm estimate of what the frequency of NTRK fusions is across cancer, but in most of these common adult solid tumors, we estimate that about half a percent of all the cancers that we think of commonly—breast cancer, colon cancer, pancreatic cancer, lung cancer—will harbor TRK fusions.

We’re just beginning to understand what the true genomic landscape of TRK fusion-positive cancers is. Looking at our experience at Memorial Sloan Kettering Cancer Center in about 80 TRK fusion-positive patients, we rarely, if ever, find concurrent classic drivers like KRAS, NRAS, BRAF, or any of the RTK [receptor tyrosine kinase] mutations like EGFR, ROS, or ALK. So it really does seem in the overwhelming majority of cases that when you have NTRK fusion, that’s mutually exclusive with other canonical drivers of that cancer type. We certainly know even less about the concurrent expression of PD-L1 [programmed death-ligand 1] and NTRK fusion-positive cancers. But I think that because the presence of an NTRK fusion is such a powerful predictor of response to NTRK inhibitors, most of these patients really ought to preferentially be receiving NTRK inhibitors before alternative targeted therapies might be considered.

When a cancer cell acquires a TRK fusion, the downstream consequence of that is overexpression of this fusion transcript and constitutive signaling of the TRK kinase domain, leading to uncontrolled cell growth, metastasis and cancer progression. What the TRK inhibitors are able to do is inhibit that wild-type TRK kinase in the TRK fusion and just shut off that constitutive signaling event. The scientific rationale is very similar to what we’ve seen with other targeted therapies in other kinase fusions like ALK or ROS. We know that this is an oncogenic event that leads to uncontrolled cell growth and can be targeted selectively with inhibitors designed to block this fusion.

Transcript Edited for Clarity

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