Yeah, so we had the pleasure of participating in a couple of different sessions. We had an educational session where we reviewed the now increasingly complex landscape of resistance to CDK4/6 inhibitors. Now, remember, these drugs entered widespread clinical practice almost exactly 10 years ago, and we now have three approved CDK4/6 inhibitors, palbociclib, ribociclib, and abemaciclib...
Yeah, so we had the pleasure of participating in a couple of different sessions. We had an educational session where we reviewed the now increasingly complex landscape of resistance to CDK4/6 inhibitors. Now, remember, these drugs entered widespread clinical practice almost exactly 10 years ago, and we now have three approved CDK4/6 inhibitors, palbociclib, ribociclib, and abemaciclib. These drugs have positive data in the first-line metastatic setting with an aromatase inhibitor, in the second-line metastatic setting, typically with fulvestrant, in the adjuvant high-risk setting in combination with different antiestrogens, and even recently in the HER2-positive frontline maintenance setting. So we’ve seen continued expansion and widespread deployment of these drugs across multiple tumor types in multiple stages. So what we wanted to do during this educational session was take a step back over 20 or 30 minutes and try to summarize many, many years of translational work. And I tried to highlight the perspective of optimal translational modeling using clinical samples, either from institutional databases, clinical trial assessments, or even real-world databases to look at different genomic factors that are associated with response or resistance, and then to look at laboratory modeling, where we grow the cells in vitro and we expose them to drug or we manipulate the cancer cells to overexpress or knock out specific resistance drivers. And we tried to choose examples of different genomic and molecular alterations where we have very strong data across that spectrum, from the bedside all the way to the bench and back again. I also wanted to make a point that there are many different resistance drivers to CDK4/6 inhibitors where there are multiple roads that the cancer cell can take to cause similar disruption. For example, there are many different avenues toward CDK2 activation, CDK6 upregulation, RB1 tumor suppressor loss, activation of AKT/mTOR signaling, activation of RAS/MAP kinase signaling. So we spent a few minutes with each of those and demonstrated a variety of translational research efforts showing all of the different ways that tumor cells might evolve to converge on the same molecular target, many of these alterations may not be detected by just conventional targeted sequencing of circulating tumor DNA. Some of these things happen at the transcriptional level. Some of them happen at the epigenetic level. Many of them might be missed because it’s a copy number change that’s not readily detected on widespread use of ctDNA technology. So I think we wanted to highlight the complexity of this process, convergent evolution toward multiple mechanisms of resistance, the fact that many of these things may be occult or missed on conventional sequencing, and highlight the importance of these translational research efforts and some of these newer technologies that are going to be entering clinical practice, RNA sequencing, epigenetic methylation sequencing, to start to layer on a deeper and more nuanced understanding of these targets, which afford opportunities for treatment with AKT pathway inhibitors, with RAS pathway inhibitors, with next-generation CDK2 inhibitors. So we need to understand resistance better. We need to have a really high-throughput way for oncologists, whether they be academic or community practice, to identify these changes in patients. And we need to have the right therapeutic approach immediately ready to be utilized in those situations.
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