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COMy 2026 | How do tumor subclones and T-cell dynamics influence ibrutinib responses in Waldenström’s?
Steven Treon, MD, PhD, FRCP, Dana-Farber Cancer Institute, Boston, MA, shares insights from a Phase II study (NCT02604511) evaluating the influence of tumor subclones and T-cell dynamics on ibrutinib responses in patients with Waldenström’s macroglobulinemia (WM) across 5 years. Dr Treon explains the mechanisms by which tumor cells evade BTK blockade, highlighting that the degradation of HCK and BTK may help overcome resistance-associated mutations. This interview took place at the 12th World Congress on Controversies in Multiple Myeloma (COMy) in Paris, France.
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Transcript
Yeah, I think this is a very important study. It was just published in Blood. We have a very young, dedicated physician scientist who’s been working on this project. And the long and short of it is for five years, we serially followed patients who were being treated on a frontline ibrutinib monotherapy trial. What we learned actually is very interesting is that, you know, tumor cells actually use, you know, a different mechanism to overcome the BTK blockade induced by ibrutinib...
Yeah, I think this is a very important study. It was just published in Blood. We have a very young, dedicated physician scientist who’s been working on this project. And the long and short of it is for five years, we serially followed patients who were being treated on a frontline ibrutinib monotherapy trial. What we learned actually is very interesting is that, you know, tumor cells actually use, you know, a different mechanism to overcome the BTK blockade induced by ibrutinib. What we see actually is that lyn, which is a member of the src family, begins to kick in and take over, and you start seeing overexpression of lyn. And we actually modeled this in our laboratory, showing, in fact, that in these ibrutinib-resistant cells, by knocking down lyn, one could reintroduce sensitivity. We’ve actually furthered this work now. We presented at ASH actually some very exciting models around BTK-mutated disease. And what we’re finding is that another src family member, HCK, is also casetting in and doing actually the transmission of survival signaling in response to MYD88 when in fact you’ve disabled BTK. Now, what’s important to recognize is, yes, you know, our BTK inhibitors disable kinase activity, but still there’s a scaffold there that, you know, continues to function and bring in these src family members. And the work that we’re doing right now is to try to degrade HCK in order to, and BTK, in order to take away that scaffold. So that work is very exciting because it’s showing us that we can overcome these BTK mutations. And this is now, you know, important across all the BTK inhibitors, not just, you know, the covalent ones, non-covalent ones like pirtobrutinib, but also we’re seeing this with BTK degraders. So we do have to target now this, you know, this upstream complex that’s allowing for growth survival signaling to continue.
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