Resensitizing Triple-Negative Breast Cancer: Targeting the YES1 Protein

Podcast Transcript

Dale Shepard, MD, PhD: Cancer Advances, a Cleveland Clinic podcast for medical professionals. Exploring the latest innovative research and clinical advances in the field of oncology. Thank you for joining us for another episode of Cancer Advances. I'm your host, Dr. Dale Shepard, a Medical Oncologist, Director of International Programs for the Cancer Institute at Cleveland Clinic and Co-Director of the Cleveland Clinic Sarcoma Program.

Today I'm happy to be joined by Dr. Ruth Keri, Associate Director for Basic Research in the Case Comprehensive Cancer Center and Professor of Cancer Biology. She's joined us a little over a year ago to talk about YES1 inhibitors for treating patients with triple-negative breast cancer and that episode is still available. She's here today with an update to discuss how blocking the YES1 protein resensitizes triple-negative breast cancer for treatment. So welcome back.

Ruth Keri, PhD: I'm glad to be here.

Dale Shepard, MD, PhD: So, I gave your title but give us a little bit of an idea of what you do here at Cleveland Clinic.

Ruth Keri, PhD: So, I lead the Breast Cancer Center of Excellence at the Lerner Research Institute, and the goal of that center is to provide support for collaborative research projects across the enterprise so that we can discover new ways to treat the spectrum of diseases that are known as breast cancer. I'm also the Associate Director for Basic Research in the Case Comprehensive Cancer Center, which is a three-institution collaborative program. It includes the Cleveland Clinic, Case Western, and University hospitals, all as equal partners as we advance cancer science in Cleveland and globally.

Dale Shepard, MD, PhD: Excellent. Well, we're going to talk about YES1, we're going to talk about triple-negative breast cancer. Let's kind of reset the stage a little bit. We talk about triple-negative breast cancer, and I know you are on the basic science side but give us a little bit an idea of why this is particularly hard to treat.

Ruth Keri, PhD: Yeah, so triple-negative breast cancer is defined by what it lacks. It lacks an expression of estrogen receptor, progesterone receptor, and HER2. And because of that, those tumors are not responsive to the standard toolkit of therapies that we have that are targeted therapies. And as a result, patients get treated with cytotoxic chemotherapies, a little bit of immunotherapy, but generally these drugs either work or they don't in patients. So about 50 percent of patients will recur and when they recur, they have very aggressive disease that is very difficult to treat. The other thing that's I think particularly interesting or important to think about for triple-negative breast cancer is that it shows racial disparities. African-American women are more likely to develop this disease and also younger women are more likely to develop this disease. And so it's kind of one of those diseases where we really need to figure out what drives it so that we can identify new targets and new drugs for treating it.

Dale Shepard, MD, PhD: And so we have talked before about YES1. Give us a background here and remind us what that is and why it's important.

Ruth Keri, PhD: So there are a group of proteins called Src family kinases. And YES1 is a member of that group. Now the group is called, or named after Src because it was the first one discovered. And actually that discovery led to the award of the Nobel Prize in 1989 because it was the first what we call oncogene. So it was the first one discovered that where a gene when it's dysregulated or mutated can actually cause cancer. So it was thought that there was one of these, but then there's actually nine of them. And YES1 is one of them. Now because we found out that Src drives cancers, this started right away the development of therapeutic design to inhibit this protein. Well, unfortunately, these drugs block all of the family members, so they have severe dose limiting toxicities in patients. And we thought, "Well, if we could identify individual members and what they do, maybe this would reveal a way to target just one of them. Eliminate those toxicities, but still have effectiveness in cancers that were dependent on them."

Dale Shepard, MD, PhD: Are there particular normal cells, cells that aren't cancers that tend to express more of these receptors?

Ruth Keri, PhD: The different receptors... They're actually non-receptor tyrosine kinases. They are drug receptors I guess, but the different cells express different amounts of these different proteins and they have different dependencies on them. The most interesting thing for us for YES1 is that if you take a mouse and you completely eliminate this gene, the mice are pretty normal. So that suggests that you could have a very broad therapeutic window to target this particular kinase that seems to be overexpressed in triple-negative breast cancer, but not impact the rest of the body. At least that's the goal.

Dale Shepard, MD, PhD: And what role does this protein play on inhibiting tumor growth and what kind of role does it play on chemotherapy resistance?

Ruth Keri, PhD: So our first foray into this study was just looking at all the different Src kinases and which ones might be overexpressed in triple-negative breast cancer. YES1 is overexpressed, it's associated with worse patient outcomes in patients that have tumors that overexpress it. And we found that high levels of YES1 are associated with worse response to the combination therapy of taxanes and anthracyclines. So this suggested that maybe that YES1 controls in some way the aggressiveness of cancers and their response to chemotherapy. So we did the standard thing that basic scientists do, we knocked it out in cells and saw what happened. And it was a surprise to us because we saw that their nuclei were all misshapen, crazy, broken up. And this suggested to us that there was something that YES1 does that really controls the way the nucleus forms.

Now one of the things nucleus does is when you go through cell division, you duplicate your DNA and you have to segregate your DNA into the two daughter cells. And if you don't do that properly, then you'll get really weird shaped nuclei. So we started to think, "Oh, this thing controls how cells divide." And in fact, it does, it regulates the production of an organelle in the cell called centrosomes that really cause the separation of the DNA into the two daughter cells.

Dale Shepard, MD, PhD: Since that centrosome concept is, for cell division, so important for normal cells, but also lots of tumors, does this seem like it's something that can be applied to other cancers as well?

Ruth Keri, PhD: Yeah, actually, well, we don't know about its regulation of mitosis, but we do know another thing that YES1 does, and this was a complete surprise to us, is it regulates the levels of a receptor called epidermal growth factor receptor or EGFR. And it does this both in triple-negative breast cancer cells as well as non-small cell lung cancer cells. So lung cancer is kind of the poster child for EGFR inhibitors. And so we thought, "Oh, well, maybe targeting YES1 will improve the responsiveness of lung cancer cells to those inhibitors." And in fact it does. And in triple-negative breast cancer, they have lots of epidermal growth factor receptor, but for some reason they don't respond as well to the drugs. It's probably because you have to give so much drug that you get into the toxic range before you can actually inhibit the growth of the cancer. So what we found is that the YES1 controls how much EGFR you have in the tumor cell and by reducing YES1, you reduce EGFR and that sensitizes the cells to EGFR inhibitors. So this might be an avenue for revisiting EGFR inhibitors in triple-negative breast cancer if it was combined with say, a YES1 inhibitor. At least in mouse models that we've done both with lung and breast cancer, it seems to work.

Dale Shepard, MD, PhD: So, a lot of people listening in may not remember or have learned about the taxanes and the anthracyclines work.

Ruth Keri, PhD: Yeah.

Dale Shepard, MD, PhD: How specifically, you told us a little bit about how YES1 works in cell division. How does that complement the chemotherapies that we typically use for this cancer?

Ruth Keri, PhD: Taxanes work by messing up mitosis as well. So one of the things that they do is prevent... There are these structures called microtubules, and those are what pull the chromosomes apart, make sure that each daughter cell gets the right number of chromosomes. Taxanes mess that up. Now, it's been shown recently that if a tumor cell has kind of a compromised ability to separate their chromosomes, taxanes work much, much better. And so the idea here was if the yes one inhibitor causes that problem, you are basically sensitizing your tumor cells to that taxane effect. And so when we saw that there was problems with mitosis, it immediately made us think that it could work with taxanes and improve their efficacy. And that's actually what panned out in, again, several mouse models.

Now, why would this make taxanes better? First of all, it will sensitize the tumor cells, but secondly, the major toxicities from taxanes, one of the most important ones is peripheral neuropathy where you have nerve damage and you get tingling in your hands and feet and you can also get deafness from taxane therapy. But this is because nerves use those microtubules in a different way and the taxanes inhibit those microtubules versus dividing a cell. And so we think that you will be able to reduce the dose of taxanes, make the cancer cells really sensitive to it, and that should reduce the toxicity that is observed in the patient's nerves.

Dale Shepard, MD, PhD: So hopefully something that's as effective or even more effective with less toxicity.

Ruth Keri, PhD: Yeah, yeah, exactly.

Dale Shepard, MD, PhD: What about other drugs that might work by similar mechanisms? Have you been looking at other kind of drug combinations?

Ruth Keri, PhD: Yeah, we stuck with taxanes because that's a standard of care for triple-negative breast cancer. But I think it's likely that it would also sensitize to other agents, perhaps DNA damaging agents. We have not gone that route yet because we focused on the EGFR, but that paper is hopefully going to get accepted very soon, so it's time to start looking at other therapies.

Dale Shepard, MD, PhD: And so where are we in terms of getting something that can be put into a clinical trial?

Ruth Keri, PhD: Well, it's been really hard to get drugs that selectively inhibit one of these proteins versus the whole group of them. But this company called Nuvectis has used a very different approach to targeting YES1, and they have an inhibitor that inhibits just YES1, and also Src. That inhibitor just entered phase I safety studies in, I think it was October of 2023. And I think they're supposed to finish their accrual of a target of 40 patients in April of next year. So we'll see then if at least their agent is safe, and then they'll start going into studies looking at efficacy. That's the only one that I know of that is in clinical trials. And I think it's because they targeted a very different part of the protein than what people standardly do, which is try to target the kinase.

Dale Shepard, MD, PhD: What has been the biggest barrier? Has it been toxicity or just getting something that's able to be given in the first place?

Ruth Keri, PhD: It's the selectivity. It's really hard to... So generally when you develop drugs, you try to inhibit what's the enzymatic activity. So the enzymatic activity of all these things is the kinase, which means they all bind to ATP and almost all these molecules look like ATP. They're ATP analogs. And so that just makes it very hard for specificity. And that's not just true for the Src kinases, that's true for small molecule inhibitors of EGFR, of many other kinases. So what Nuvectis did is they went to an allosteric site of the protein that's different than the other Src family kinases. And that I think is probably a good approach. Another approach, which I haven't seen anybody execute, but I think would work is develop a molecule called a PROTAC, which actually binds to your target and degrades it, gets rid of the protein instead of trying to inhibit the enzyme activity because trying to inhibit the enzyme you're going to have off-target effects and toxicity.

Dale Shepard, MD, PhD: So certainly, making good progress with YES1 is a pathway. When we think about this whole field and these sort of proteins and their importance, what either in your own lab or things that are coming along are most exciting right now?

Ruth Keri, PhD: Well, for YES1, we just got a new grant, so we're just starting out this study. One of the things we noticed is when you look at the pattern of expression of YES1 in human tumors, it's patchy. Not all the cells have YES1. And so if you just grind up a tumor and ask for what the activity is, you're not really getting the full story, right? You're getting some average kind of information. And so what we're doing now is a study called spatial transcriptomics where we can actually look at the individual cells that have YES1 activity and ask how are they different than the cells that don't have YES1 all in the same tumor? And so what this will tell us very clearly, I hope, is what is YES1 doing in those particular tumor cells? And that will give us, I think, more insight about how it works and again, more targetable downstream effectors of the kinase.

Dale Shepard, MD, PhD: And I guess anytime you have more of this patchy sort of distribution, you always worry about clones of tumors that might not get affected by therapy.

Ruth Keri, PhD: Yeah, exactly.

Dale Shepard, MD, PhD: Any thoughts that like combining with an immunotherapy or something that might be activated by cell kill might be effective?

Ruth Keri, PhD: So, we have done a little bit about immunotherapy because when you mess up mitosis and you'll get lagging chromosomes that kind of form these little mini-nuclei, they're called micronuclei, and those things just are not very stable and they kind of leak DNA, and this activates the intrinsic immune pathway in tumor cells. And that's thought to perhaps stimulate immune recognition. So we did a study, again, this is just in mice, but we did a study where we used the inhibitors to YES1 both in mice that had an immune system in mice that didn't have an immune system. And the drugs work much better in mice that have an immune system. So we think that there is a relationship, we are really in early days trying to figure out what that is.

Dale Shepard, MD, PhD: Isn't that what makes it fun? There's always more questions.

Ruth Keri, PhD: Yes. The more you learn, the more you don't know.

Dale Shepard, MD, PhD: Well, you're certainly making great progress with YES1, appreciate you giving us some updates and we'll look forward to continuing to hear more about the story. Thanks for being with us.

Ruth Keri, PhD: Yes, it has been great being here. Thank you.

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