TRK Inhibitors: A Tumor Agnostic Targeted Therapy - Episode 1

Evolution in Cancer Treatment: Tropomyosin Receptor Kinases

January 28, 2019

Shubham Pant, MD:Welcome to this Targeted Oncology™ presentation ofPrecision Medicine in Oncology® called “TRK Inhibitors: A Tumor Agnostic Targeted Therapy.” I’m Dr Shubham Pant, a medical oncologist at MD Anderson Cancer Center in Houston, Texas. I’m here with my colleague, Dr David Hong, deputy chair of the Department of Investigation Cancer Therapeutics and associate vice president of clinical research, also at MD Anderson.

Targeted therapies have really come to the forefront of the treatment of cancer. Today we are going to talk about an important new therapeutic class that has shown great promise among several advanced malignancies called TRK inhibitors. These agents represent a paradigm-changing advance in precision oncology and drug development for rare mutation-driven cancers. Dr Hong, welcome to the program.

David S. Hong, MD:Thank you for inviting me, Shubham.

Shubham Pant, MD:That’s great. So first tell me, this is a brand-new kind of science and oncology. This is a very different tumor agnostic approach, which has come to the forefront nowadays in oncology. These new drugs have been recently approved. So first tell me, what are these tropomyosin receptor kinases? What are these TRKs? What is it?

David S. Hong, MD:It’s a really good question. These receptors have been known for a long time, and in the normal human functionality, they serve as receptors to modulate neurologic functions. For example, TRKA is involved in things like temperature regulation, pain. TRKB has a number of other functions. It helps regulate movement. To some extent, it regulates weight. Lastly, TRKC is oftentimes involved in proprioception. And it wasn’t until the 1980s that we first identified that certain cell lines, colorectal cell lines, actually had TRK fusions that would really constitutively and oncogenically make these cells drive cancer.

Shubham Pant, MD:So the genes, what are the genes that actually have these fusions, and how does it lead to protein creation?

David S. Hong, MD:The genes areNTRK1, NTRK2,andNTRK3. And what ends up happening is that in the development of a cancer cell, there’s an actual fusion or translocation where the 3-prime end of theNTRKgene then fuses in a way with the 5-prime portion of another, a partner gene. And therefore, it leads to a receptor that is in a way constantly on. It’s a growth signal for that cancer cell.

Shubham Pant, MD:What you are saying is that you have the fusion and that turns a switch on, which is normally off, and that causes these cells to divide.

David S. Hong, MD:Correct.

Shubham Pant, MD:And then they created the protein cells, right? The TRK A, B, and C proteins?

David S. Hong, MD:Correct. And this signals to a number of oncogenic pathways such as the MAP [microtubule-associated protein] kinase pathway, and also PI3 kinase, etc.

Shubham Pant, MD:So normally—this is when they are dysregulated in humans and everything—it’s used for normal human development.

David S. Hong, MD:Correct.

Shubham Pant, MD:But when they’re dysregulated, they can lead to cancer. So that’s very interesting. So tell me, how would you inhibit these pathways? What is the best way to inhibit these pathways? If they are in humans and causing cancer, how would you inhibit these pathways?

David S. Hong, MD:So what others have discovered is that the best way to inhibit these pathways is to really inhibit that ATPase [adenosine triphosphatase] pocket, these aberrant TRK receptors used to drive the signaling. And so recently—obviously we’ll be talking about larotrectinib, entrectinib—there have been drugs, previous drugs, that have sought to target that ATPase kinase pocket.

Shubham Pant, MD:And that’s the cancer cell.

David S. Hong, MD:Yes.

Shubham Pant, MD:You’re saying the fusion is on, so the switch is on. It’s creating this protein, so you’re trying to block it at the level of the tumor cell.

David S. Hong, MD:Yes, correct.

Shubham Pant, MD:So people made these inhibitors to target that pocket exactly. And what does it do? If it fits into it, what does it lead to?

David S. Hong, MD:Well, it leads to inhibition of that ATPase pocket. Therefore, there’s no downstream signaling of that signal or the other receptor.

Transcript edited for clarity.