Loss of SYNCRIP Unleashes APOBEC-Driven Mutagenesis, Tumor Heterogeneity and AR-Targeted Therapy Resistance in Prostate Cancer - Ping Mu

August 14, 2023

In this discussion, Andrea Miyahira speaks with Ping Mu about his group's paper. The research focuses on the role of SYNCRIP in controlling APOBEC-driven mutagenesis in prostate cancer. Dr. Mu explains that the loss of SYNCRIP leads to a break in the mechanism controlling this mutagenesis driver, resulting in prostate cancer gaining resistance to AR therapy. The conversation highlights the tumor heterogeneity that often arises as tumors become more resistant and how APOBEC proteins, which cause mutations in the tumor genome, are involved. The identification of SYNCRIP's crucial role in controlling APOBEC-driven mutations offers significant implications for potential therapy. They also discuss translational therapeutic approaches, including early-stage treatment with APOBEC inhibitors and the possible connections with immunotherapy and DNA damaging drugs. The conversation concludes with both expressing interest in future research directions and acknowledging the translational potential of the findings.


Ping Mu, PhD, UT Southwestern Medical Center, Dallas, TX

Andrea K. Miyahira, PhD, Director of Global Research & Scientific Communications, The Prostate Cancer Foundation

Read the Full Video Transcript

Andrea Miyahira: Hi everyone. Thank you for joining us today. I'm Dr. Andrea Miyahira at the Prostate Cancer Foundation. Today I'm joined by Dr. Ping Mu, an assistant professor at the UT Southwestern Medical Center to discuss his group's recent paper, Loss of SYNCRIP Unleashes APOBEC Driven Mutagenesis, Tumor Heterogeneity in AR Targeted Therapy Resistance in Prostate Cancer, recently published in Cancer Cell. Thanks for joining me today, Ping.

Ping Mu: Thank you Andrea for the nice introduction. My name is Ping and I'm an assistant professor at UT Southwestern and today I'll use the next five minutes just to tell you a little bit about our recent work, which is called Braking Bad, it's a very fancy title. I think we find the molecular brake which controls the APOBEC driven mutagenesis in prostate cancer. And when this brake is going to break, it's like causing loss of the mechanism to control this mutagenesis driver of APOBEC, then prostate cancer gains resistance to AR therapy.

So as we all know, like the prostate cancer research community, we can actually manage early stage primary prostate cancer pretty well. However, no matter how we manage prostate cancer with many therapies, like castration therapy or NextGen AR therapy, many patients eventually still going to develop resistance to anti-androgens as any therapies targeting the AR signals. And we are really interested to understand why and can we develop new therapy to reverse or overcome the resistance?

And one of the key finding in recent years of the cancer research field is that almost always the case, the more the tumor become resistant, the more heterogeneity it become, we got more and more heterogenesis tumor in the resistant tumor. And why is that? I would like to use this tree of heterogeneity to display, what is tumor heterogeneity? We can see tumor heterogeneity at many levels. For example, the most basic level as pathological, we have tumors could be luminal or double negative or neuroendocrine, but one level deep down is transcriptomic level. Sometime we say tumor could be driven by androgen receptor or BRN2 or ER or MYC. But most important heterogeneity happened in the core of the tumor, which is the genomic level. We know that the tumor could have mutations anywhere in different genes and many of those mutations are the reason cause resistance.

And we want to know why cancer cells could gain all those mutations in a very short period of time. Of course we know that DNA repair deficiency or genomic instability could all cause mutations, but that accumulation normally takes time. Cannot explain why a lot of time, the resistant tumor comes out really quickly and then they have a hot pot of mutations. And is that possible? Cancer cells actually have a mechanism which to quickly gain mutations and become resistant by itself. And I think yes, there is one family or protein in recent years, got a lot of attention, which is called APOBEC proteins. So this APOBEC protein is a type of a DNA deaminase. What happens is this family or protein will cause a C to U change in a single strand DNA and after the DNA repair will cause the CG to TA mutation and this mutation are everywhere in our tumor genome. For example, has been identified in more than 70% of human cancer and more than 50% of cancer genomes.

However, key questions remain. First is, for example in prostate cancer patients, we see a lot of driver mutations but we don't know where those driver mutations come from. And second, it's quite interesting. We in our body, we have such a strong mutation engine, is APOBEC protein and we don't know how our cell actually originally controls this mutation engine. And how come this mechanism got lost in later stage prostate cancer and make this tumor got so many mutations. And then in this recent work we published actually last week, we think we find this crucial mechanism or this molecular brake. This protein's name is SYNCRIP and this gene actually is very frequently deleted in prostate cancer patients. Around you can see with heterozygous and homozygous lesions, could be as more as 50% of patients. And more interestingly, if you check the patient response to anti-androgen therapy, if you have a SYNCRIP deletion, then this patient will very unlikely respond to anti-androgen therapy and their a drop is minimal.

Basically simply if they lost SYNCRIP, they don't respond. Why is that? Through a lot of work, we actually find that a SYNCRIP, which is this protein down here, could interact with APOBEC family proteins stuck into the DNA binding hook of this protein and stop APOBEC binding DNA and cause all the mutations. And as we show that in prostate cancer cells, if we lost the SYNCRIP, we will have a thousand times high of APOBEC caused mutations. And that's also happening in patients. If we just separate patients based on their genomic status of SYNCRIP, you can say when we have a lot of SYNCRIP copies such as the amplification or wild type, you have very minimal APOBEC cause mutation. But if you lost the SYNCRIP, you've got so many APOBEC mutations and this mutation are the reason for little resistance.

And then we combined a lot of cutting edge technologies including single cell sequencing 3D organoid culture and we follow all the tumors who carry those mutations and see where are those mutations go and which gene it actually mutated. And quite interesting, we find APOBEC caused mutation in some very well-known frequently mutated genes including FOXA1, EP300. And we show that those mutations are the reason for resistance.

So this figure is, my last slide, actually very well summarized what happens. When we have a wild type SYNCRIP, like a primary prostate cancer, the mutation ratio is very low. So the tumor responded to all the therapy we gave to them. However, when SYNCRIP was lost in many patients, the APOBEC got loss of control and start causing all mutation everywhere. And you can imagine, this is almost like a seed of fuel of resistance because you have mutation everywhere.

Then when we treat this tumor with therapy, we are selecting out all those mutations, with little resistance, which explain why we have this mutation resistant tumor so quickly. And I think the last key part I want to emphasize is, we actually have a new class of drug called APOBEC inhibitors. And if we treat the tumor with SYNCRIP deletion at a very early stage, we can actually stop this mutation engine from even causing uncontrolled mutation, to slow down any possible new residual tumor to show up. So I think this definitely has a very huge translational potential for the precision medicine practice in prostate cancer. And thank you very much.

Andrea Miyahira: So thank you for sharing that Ping. I had some questions about your paper. So do SYNCRIP deletions co-occur or not with other DNA repair alterations such as DDR, MMR, CDK12?

Ping Mu: That's a beautiful question. Yes. SYNCRIP deletion actually is on 6Q. 6Q, this fragment in prostate cancer is a very large region of deletion and there are several genes which I know are  related to DNA deficient repair. And also another data we showed in the paper, which I don't have time to show today, is that beside APOBEC signature mutation, when SYNCRIP is lost, there is a huge chunk of mutation that are caused by DNA repair deficiency. So which means it's very possible that low SYNCRIP low tumor, would be more sensitive to any immunodeficiency drug like PARP inhibitors, but we need to confirm that.

Andrea Miyahira: Okay, thanks. And what mechanisms does APOBEC3B use to drive the specific genome alterations noted such as FOXA1 mutations targeted to these genes specifically, or is the tumor background selecting these?

Ping Mu: That's a beautiful question. So technically APOBEC always recognizes a specific domain in the DNA, which is called a TCW domain. It always edits that scene in the domain. However, you can imagine this domain is everywhere in the genome. So technically APOBEC is like an uncontrolled machine to cause mutation, but it didn't really select any mutations. However, the drug or the therapy we give patients are the selection. APOBEC basically is like a fuel which pumps gas into the car and then the car can drive. So those selections make those mutations, for example on FOXA1 or EP300, eventually got enriched in the population, which we show it very clearly from the single cell evolution analysis.

Andrea Miyahira: Thanks. And are there possible translational therapeutic approaches, for instance, the translational plans for inhibiting APOBEC3B?

Ping Mu: That's a wonderful question. So there are several APOBEC inhibitors that have been developed, which are two of them we have tested in the paper. However, the problem is many of those inhibitors, even the one we tested, have been shown to be not very highly specific. So our paper first, I think it show a very cool part of it, is even we just use a very small fragment of SYNCRIP, like around 180 amino acids, putting back into the cell. We can restore this blockage to restore this broken brake.

And then another key thing I want to emphasize is you can imagine if SYNCRIP is already out of control, then cause a lot of mutation, then you inhibit APOBEC wouldn't work because mutation is already there, which means we perhaps need to select the patient at an early stage based on their expression level of SYNCRIP, to use SYNCRIP as an early biomarker to select patients and say if you don't have SYNCRIP or your SYNCRIP is very low, then most likely, you will have some mutation at years later when we treat. So we should treat with APOBEC inhibitor at a very early stage to stop this everlasting cancer evolution.

Andrea Miyahira: Thank you for that. Are there any next steps in your research that you'd like to share?

Ping Mu: Yes. So we're working on this SYNCRIP and APOBEC interaction with mouse model and other stuff. So one of the key future directions is, if you think about it, APOBEC out of control caused so many mutations and small fragmenting DNA, which means they most likely are going to activate some immune response, right? So we're really interested to understand if APOBEC loss of control, will cause any different response to immunotherapy blockage like PD-1 inhibitors, make it more sensitive or actually less sensitive. And also as your first question, we want to test if SYNCRIP loss will make the tumor more sensitive to DNA damaging drugs and we can do anything to really slow down the therapy resistance and benefit patients.

Andrea Miyahira: Well thank you so much for coming on here with me today and sharing this really intriguing study.

Ping Mu: Thank you Andrea. Thank you for the great questions.