How CDK4/6 Inhibitors Made a Comeback

Sometimes pre-clinical studies show that a drug has a good chance of helping patients, but when the drug is tested on patients, it doesn’t work as expected. Today, we are talking to Dr. Shom Goel, Group Leader and Medical Oncologist at the Peter MacCallum Cancer Centre and the University of Melbourne, in Australia & Komen-funded research scientist. He will talk with us today about the history of CDK4/6 inhibitors – how they initially failed but how scientists continued to work with them and are now seeing some positive results in patients.

Dr. Shom Goel is a Group Leader and Medical Oncologist at the Peter MacCallum Cancer Centre and University of Melbourne, in Australia. He is also a Komen-funded research scientist.

Here is a transcript of the show:

Adam Walker (00:03):
From Susan G Komen, this is real pink, a podcast exploring real stories, struggles, and triumphs related to breast cancer. We’re taking the conversation from the doctor’s office to your living room. Sometimes preclinical studies show that a drug has a good chance of helping patients, but when the drug is tested on patients, it doesn’t work as expected today. We’re talking to Dr. Sean gold group leader and medical oncologist at the Peter MacCallum cancer center and the university of Melbourne in Australia and Komen funded research scientist. He will talk to us today about the history of CDK four, six inhibitors, how they initially failed, but how scientists continued to work with them and are now seeing some positive results in patients Dr. Goel, welcome to the show.

Dr. Shom Goel (00:50):
Thanks for having me great to be here.

Adam Walker (00:52):
Well, I appreciate you. You, you traveling virtually to meet with me such a long distance. I’m excited to talk to you, so let’s start out. Can you start by explaining to our listeners, what is CDK four, six inhibitors, and what are they used for

Dr. Shom Goel (01:08):
Sure. So CDK four, six inhibitors, a really exciting class of drugs that we’re using to treat breast cancer these days. The way I think of it, we all know that cancers are made up of millions of little cells. And if you think about it for one of those cancers to grow, those cells need to divide. One becomes two, two becomes four. And whenever a cell needs to divide, whether it’s a cancer cell or a normal cell, it has to go through something that we call the cell cycle. It’s a series of steps that it goes through. So it doubles everything inside and it splits in half to get to daughter cells. And this process of going through the cell cycle is, is really tightly controlled, even in cancer cells, by these proteins that we call CDKs that stands for cyclin-dependent kinases. And it turns out that in many breast cancers, two of the CDKs CDK four and CDK six are really important in controlling the way breast cancer cells divide. So what these drugs are CDK four, six inhibitors they’re drugs that are designed to block those CDKs from working. And so therefore try to stop breast cancer cells from dividing.

Adam Walker (02:22):
Oh wow. That’s fascinating. And that was a kind of perfect description of what they do. I, I, I really appreciate that. So so I know there’s been some recent news around CDK four, six inhibitors. Do these drugs hold promise in helping breast cancer patients?

Dr. Shom Goel (02:41):
Oh, most definitely. In fact, we’re already using a number of these CDK four, six inhibitor drugs in our clinics today in the U S in Australia and in much of the world at the moment we’re using these medicines for a type of breast cancer called hormone receptor positive breast cancer. That’s the type of cancer that’s we think of as being driven by estrogen. And we’re really using them for patients who have metastatic hormone receptor positive breast cancer. So when the cancer spread to other parts of the body typically we would treat that disease with what we call hormonal therapy anti-estrogen therapy. But what we now know is that if we add a CDK four, six inhibitor to that, it makes a huge difference. It makes the hormone therapy work a lot better, the drugs work for longer, and in some cases, people, people live for longer as well. So they’ve definitely made a huge impact on the way we treat breast cancer today. And recently that these drugs are starting to show a number of other new and interesting effects in different types of breast cancer. And, you know, I predict that in the years to come, we’re going to be using them in a number of other types of breast cancer and other situations as well.

Adam Walker (03:51):
Wow, that’s fantastic. And that’s very good news, I think for the breast cancer community. So I know CDK four, six inhibitors have a complicated history. There were some issues with these drugs initially when they were tested on patients. Can you talk a little bit about that history for us?

Dr. Shom Goel (04:08):
Yeah, it’s actually really interesting. So, you know, this process of cell division that I spoke about before, I mean, we’ve known about that for a long, long time. And so it’s often been discussed that if we could get a drug that would block these CDKs, it would be great going back sort of 20, 25 years, there were some drugs around that did that. But turned out when those drugs were given to patients they were just too toxic. People would got too many side effects were too unwell. And so those drugs had to get thrown away. The reason those drugs, the old drugs weren’t so good. There was a couple of reasons, I guess, and this is important when we think about why the current drugs are so good. When we think about a drug in cancer, we often talk about its potency.

Dr. Shom Goel (04:58):
In other words, when it blocks CDK four and six, does it block them hard? And what we call it selectivity, in other words, does it only block CDK four and six, or does it have all these other effects that we don’t want? And if you look back at the old drugs, some of them fell down because they weren’t potent enough. They just couldn’t block CDK four and six, as much as we needed and others fell down because they weren’t selective. They were blocking all these other things inside our body and hence all the side effects. The difference now is that we now, the drugs we have now are selective and potent.

Adam Walker (05:36):
Mm, okay. Okay. That’s great. So then where do you think these drugs are going to make the most impact?

Dr. Shom Goel (05:45):
Look, I think to be fair, they already have made a huge impact. I mean, for people out there living with metastatic hormone, receptor, positive breast cancer, these, these drugs have really been game changing. But I think there’s a couple of areas to look, look to now where I think we could even see a bigger impact moving forward. The first question, which we don’t have a formal answer to yet is could we be using these drugs for people not only who have metastatic breast cancer, but even who have what we call early stage breast cancer. That means breast cancer that hasn’t spread outside. The idea there would be using these drugs to reduce the risk of a breast cancer recurrence. So in other words, cure increasing the rate of cure. So that’s one really interesting thing to look for. And the other thing is trying to find out what we can combine with a CDK four, six inhibitor, what other drugs we could be giving together with these that would make them work even better. I think these are the two avenues that I think show the most promise at the moment moving forward.

Adam Walker (06:50):
Hmm. Wow. Okay. So just I’m just curious, going back to this idea that historically they didn’t work well. There were problems with, with how it worked, but, but we continued to research, right. And so would you agree that the success story of the CDK four, six inhibitors is a great example of how research and scientific perseverance can result in better treatments for patients? Long-Term

Dr. Shom Goel (07:15):
Absolutely. That’s totally the case. I mean, you know, there are lots of, for those of us who work with these drugs and talk about these drugs a lot. There are a lot of little stories actually in the history of how these drugs were made, the old ones and the new ones were, which tell us that many times along, along the way, these drugs almost got overlooked or dismissed. But it was only through someone being very careful or being very persevering in their research that we eventually worked out how effective these drugs could be. Now that we’ve got these great drugs, it seems like a no brainer of course there, of course, they’re great. But if you look, if you look back, there was a lot of skeptic CISM about CDKs and a lot of, a lot of people being very persistent sharing knowledge step-by-step and then suddenly we had an explosion of progress.

Adam Walker (08:06):
Wow. So this, I mean, obviously this seems really important. We’ve got a pretty broad listener base. Is there anything specific that you’d like for them to know about this topic?

Dr. Shom Goel (08:19):
I think for me, it’s actually just what we touched on, which is how important it is that we remain engaged in research when it comes to breast cancer, you know, every drug, these drugs need CDK four, six inhibitors, no doubt her, some of the biggest headline drugs that we’re using in breast cancer right now. But every drug that we’re using, every new drug that comes into our clinic has only come about because of decades of research. So for example, these drugs, I told you about they, they inhibit what we call the cell cycle. The people who started studying the cell cycle, they were studying yeast and sea urchins, and they won the Nobel prize for this Manny Manny years ago. When they were doing that research, I don’t think they had cancer in the forefront of their minds at all. Right. And now here we are. So I would say to our listeners, you know, every time you see someone working in a lab or playing around with a new drug, someone studying even yeast or fruit flies or whatever, just remember that it all counts and, and research what we’re doing in them is always a key to progress.

Adam Walker (09:26):
Wow. That’s, that’s really great perspective. And it’s hard for us to see that perspective sometime this is a really good example of that. So then so last question, where do you see CDK four, six story? What do you see it going next and what excites you about that?

Dr. Shom Goel (09:43):
Yeah, I think that there’s a lot of excitement. In my mind, things we could be doing with these drugs moving forward, we still have a lot to learn. And in fact, my research lab is pretty much exclusively focused on studying these drugs. We do that because we still think there is a lot to learn. And as I said before, I think one of the big areas is trying to work out what else we could. We could be combining CDK four, six inhibitors with, to help people do even better. Another really interesting area that’s coming up is, and it’s totally out of the box and unexpected is how CDK four, six inhibitors might change our immune system in a good way, in a way that helps the immune system fight the cancer and see if we can work out how to use that in, in the way we treat patients. And I think the other big question, which we’re all focused on is this concept of drug resistance. Because even though we know CDK four, six inhibitors are great, but the truth is that in, in many people, eventually they stopped working. Right? And so we’re very focused now going back to this idea of research, to work out why that is so we can come up with the next wave of therapies to keep moving forward.

Adam Walker (10:52):
Wow, well, that’s great. Well, this is honestly been truly enlightening Dr. Goel, I really appreciate you taking the time to share this insight with us.

Dr. Shom Goel (11:01):
Oh, it’s totally a pleasure. Thanks again.

Adam Walker (11:05):
Thanks for listening to real pink, a weekly podcast by Susan G Komen for more episodes, visit real for more on breast cancer. Visit Make sure to check out at Susan G Komen on social media. I’m your host, Adam, you can find me on Twitter at AGA Walker or on my blog. Adam J