YES1 Inhibitors: A Game-Changer in Triple-Negative Breast Cancer Treatment

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 Shepherd, a medical oncologist here at Cleveland Clinic directing the Taussig Early Cancer Therapeutics Program and co-directing the Cleveland Clinic Sarcoma Program. Today, I'm very happy to be joined by Dr. Ruth Keri, Associate Director for Basic Research in the Case Comprehensive Cancer Center, and Professor of Cancer Biology here at Cleveland Clinic. She's here today to talk to us about a novel therapeutic target for patients with triple-negative breast cancer. So welcome, Ruth.

Ruth Keri, PhD: Hi, Dale. It's nice to be here.

Dale Shepard, MD, PhD: Tell us a little bit about what you do here at Cleveland Clinic.

Ruth Keri, PhD: Yeah, so I am in the Department of Cancer Biology. I moved to the Cleveland Clinic about three years ago from Case Western with the idea of building a more translational oriented breast cancer research program. As part of that activity, I lead a Breast Cancer Center of Excellence at Lerner Research Institute, and our research is almost exclusively on identifying what makes breast cancers grow and identifying ways to stop that growth.

Dale Shepard, MD, PhD: Excellent. So, we're going to be talking about a new target. You've been working on something called YES1. Tell us a little bit about that particular molecule. What is it? A little bit of background.

Ruth Keri, PhD: Yeah, sure. So, most of us like to think about cancers as being a ball of bad cells, but in fact, that ball of cells has many surrounding tissues that it receives signals from, the normal tissue that is. It also receives signals from the blood and sometimes from hormones. All of those signals are kind of like text messages, if you will, to the cancer cells iPhone. It's telling the cancer cell to grow, to pick up and move to another part of the body. Well, what YES1 is is like the iPhone. It's receiving all those signals and it's telling the cancer cell what to do.

Dale Shepard, MD, PhD: How did this particular Yes1 come to be a target of interest?

Ruth Keri, PhD: So, we found that if you have too much YES1, so too many iPhones turned on, I guess, or if it's mutated in some way, that this will give a chronic signal to the cancer cells to grow and to move. What we found in particular was this type of breast cancer called triple-negative breast cancer has very high levels of YES1. So, we started to think that maybe we could inhibit YES1 and figure out what it actually does to the cancer cells. So, we did that, and we found that YES1 is really important for cells to divide and make more cells. More importantly, YES1 helps those cells become very bad actors because as cancer cells divide, they change their DNA lot, and YES1 lets them survive that changing of the DNA and to keep growing. Then lastly, we found that YES1 is really highly expressed in cancer cells that are resistant to various drugs.

So, like I said, we focus on triple-negative breast cancer, and that disease, unlike other breast cancers, is primarily treated with chemotherapy. We'd like to have it be like other cancers where we have targeted therapies that have less toxicities, but this disease is treated with chemotherapy, associated with a lot of toxicities. More importantly, even though many of those cancers respond to therapy, a lot of them become resistant. A particular type of therapy used for triple-negative breast cancer is called Taxol or Paclitaxel or Taxotere, and those drugs are chemotherapies. It's standard of care for triple-negative breast cancer, and we found that YES1 actually allows the tumor cells to grow even when they are in the presence of Taxol. So, we thought maybe we could block YES1 and it would improve taxane response, and in fact, that's what we saw.

Dale Shepard, MD, PhD: Excellent. Just to take a really quick step backward, lots of different people might be listening in. What exactly do you mean by triple-negative breast cancer?

Ruth Keri, PhD: Oh, yeah. So, triple-negative breast cancer affects about 15 percent or so of women with breast cancer, and this is a highly aggressive disease. It's more prevalent in young women, in African American women, and it has the worst prognosis for all of the types of breast cancer. Like I said before, while we have really some great therapies for other types of breast cancer, the therapies for triple-negative breast cancer are fairly limited. There's a lot of hope for immunotherapy, but it really only works in a small percentage of triple-negative breast cancers. So, we are stuck with chemotherapy, and for now, we're trying to make chemotherapy more effective in that disease.

Dale Shepard, MD, PhD: What kind of information do we have about how YES1 allows cells to grow in the presence of taxanes?

Ruth Keri, PhD: Yeah, so like I said, when you have a cancer cell that's growing, it likes to shuffle its DNA, like shuffling cards, and it's looking for the best combination of genes that will make it grow. What YES1 does is it allows that process to happen and keeps the cells alive. Now, if you block YES1, the shuffling happens, but the cells will ultimately die because they just can't deal with that because they're losing certain genes they need for growth. When you give cancer cells taxanes or Taxol or Paclitaxel, it also messes up this shuffling that happens, and it makes the cells get very sick. If you have high YES1, it'll allow the cells to stay alive. If you get rid of YES1 by either a genetic approach or with a drug, then the taxane is really effective at killing those cells.

Dale Shepard, MD, PhD: So YES1 itself is a receptor, is that correct?

Ruth Keri, PhD: Well, it's a Src family kinase, so it talks to receptors on the surface of the cell and mediates the signals from the receptors into the cell.

Dale Shepard, MD, PhD: What have we learned so far about the ability to inhibit YES1? What kind of mechanisms, what kind of ways can we do that?

Ruth Keri, PhD: Yeah, so there are small molecule inhibitors of YES1, just like other Src family kinases. But the really interesting thing about YES1 is if you look in mouse models, for example, you can eliminate YES1, and the mouse will be just fine. So, what that tells us is that there's likely to be limited side effects if we can come up with a selective inhibitor for just YES1. Then we also know that cancer cells have too much YES1, which again, should increase the selectivity of targeting this protein. So, some drugs have been developed that are somewhat selective for YES1 and not 100 percent, but pretty good. One of them actually has just entered Phase I trials, and so we'll see how safe the drug is. We use that drug in our studies and found that it potentiates the effectiveness of Taxol.

We also in a completely different study found that YES1 potentiates the effectiveness of inhibitors of the epidermal growth factor receptor, EGFR. Now, EGFR is very highly expressed or highly active in triple-negative breast cancers but targeting it has not been very useful in patients. We're hoping that by combining the YES1 drug and EGFR drugs that will have synergy and inhibit growth, and that's what's happened in our mouse models. Then if we extend that, the poster child for EGFR inhibitors is lung cancer, and so we did studies in lung cancer and found that combining a YES1 drug and an EGFR inhibitor was also synergistic in lung cancer and in mouse model of lung cancer.

Dale Shepard, MD, PhD: So, this might end up being effective in multiple types of cancers?

Ruth Keri, PhD: Yeah, so that's one of the things we're working on now, is trying to figure out which cancers seem to be highly dependent on YES1 and which drugs might YES1 inhibitors work with particularly well. So, there might be a very broad spectrum of targets for YES1.

Dale Shepard, MD, PhD: So, when we think about these inhibitors, oftentimes we start a drug, we think we know what it inhibits, but then it inhibits five other things. Are these inhibitors unique compounds or are they things that also have been used as inhibitors for other pathways?

Ruth Keri, PhD: So, some of them are new compounds, but I would caution to say that as you said, all drugs have off-target effects in addition to their targets. So, the challenge is YES1, because it is a Src family kinase, it's really difficult to target it and not the other family members. The new drug that is in clinical trials does the inhibition in a different way. So, it seems to be more selective for YES1 and Src. One of the challenges that has happened with Src family kinase inhibitors clinically is their effectiveness in liquid tumors, but in solid tumors they've had really limited effectiveness. The reason for that is that they have dose-limiting toxicities. I think this is because you're inhibiting all of the family members, and some of the family members are really critical for normal tissue function, whereas other ones are not.

Dale Shepard, MD, PhD: You suggested earlier, YES1, we don't really know a normal function for it, so getting rid of it doesn't have a negative consequence.

Ruth Keri, PhD: Yeah, exactly. I think people have proposed normal functions, but I think there's redundancy with other Src family kinases, so you could get rid of YES1 in normal tissue, be okay. But in tumors we've used genetics to just get rid of YES1 so we know that it is the linchpin.

Dale Shepard, MD, PhD: So, what do you think is going to be the next break? You mentioned YES1 looks like an interesting target, maybe EGFR interactions. Do we think there might be some other types of receptor interactions?

Ruth Keri, PhD: Yeah, I think so. I think what we are looking for now is for this molecule that's in Phase I, whether it's actually going to prove to be safe, and then obviously it'll move to a Phase II for efficacy studies, early efficacy studies. Now, if that seems to work, then I think understanding which drug combinations to use in those trials will be important. So, the trial is all-comers solid tumors, advanced disease, but what I'd really like to see is can we use the drug in a trial where we're treating triple-negative breast cancer patients with standard of care, which is taxane, and then adding the YES1 inhibitor on top of that? Would that be the space to look at? Then as far as what we are doing in the laboratory, we are trying to figure out really how does YES1 works, which receptors particularly mediate the signals from and move from there.

Dale Shepard, MD, PhD: Are there any other types of resistance mechanisms that your lab is looking at, maybe other targets beyond YES1?

Ruth Keri, PhD: Yeah, so we are very interested in CDK4/6 inhibitor resistance. So those inhibitors are used primarily for a type of breast cancer called luminal breast cancer. They're hormone dependent, generally. When they become a little bit hormone independent, that's when CDK 4/6 inhibitors are given. Now, these drugs don't work in triple-negative breast cancer very well, but we found that we're using actually the triple-negatives to figure out what are intrinsic mechanisms of resistance, and then maybe translating those to the luminal breast cancers. But also, maybe we can get CDK4/6 inhibitors to work in triple-negative by adding other compounds.

Dale Shepard, MD, PhD: That's great.

Ruth Keri, PhD: Yeah, one of them is targeting a kinase called NEK2, which regulates mitosis.

Dale Shepard, MD, PhD: So, lots of good things coming along. Bad disease, the lack of hormonal control is significant, and then when you get chemotherapy resistance.

Ruth Keri, PhD: Yeah. Yeah. So that's why we're so focused on that is first of all, it's a very heterogeneous disease, so we'll probably need to find many different ways to treat the disease and really understanding what makes it so resistant to therapies? I'll tell you my guess is because it's very genomically unstable.

Dale Shepard, MD, PhD: I guess the genomic instability you mentioned before about immunotherapies, do you think that perhaps, of course, everyone's study is immunotherapy plus something, but in a situation like this, maybe it makes sense?

Ruth Keri, PhD: Yeah, so the first immunotherapy studies that came out showed any kind of signal in breast cancer were in triple-negative, and they were treated with taxanes. I think that that was, it might've been serendipity, but I think it really is that you're increasing genome instability and neoantigen presentation, and that's probably why it's making those tumors respond. Another approach is using carp inhibitors, which basically do the same thing.

Dale Shepard, MD, PhD: Well, fantastic. So, a bad disease, but it looks like you're well on your way to looking for some good targets for therapy. I appreciate you joining and giving us some insight today.

Ruth Keri, PhD: Yeah, thanks for having me. Really appreciate it.

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