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December 8, 2025BloodOpen Access

Diverse signaling and vulnerabilities accompany distinct BTK mutations associated with clinical resistance to COVALENT, non-COVALENT and protacs targeting BTK in MYD88 mutated lymphomas.

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Authors

NTNickolas TsakmaklisAGAlberto GüijosaSBSara J. Buhrlage

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Overview

Observational analysis reveals distinct resistance mechanisms in MYD88 mutated lymphomas, suggesting the need for tailored therapies.

Key Points

  • Engineered cell models revealed that multiple BTK mutations exhibited unique resistance profiles.
  • In BCWM.1 cells expressing A428D, M437R, and L528W, HCK activation drastically increased alongside downstream pathway activity.
  • Analysis of apoptosis indicated significant cytotoxicity from DFCI-002-06 compared to standard BTK inhibitors in resistant cell lines.
  • HCK and LYN identified as potential targets for overcoming resistance in MYD88 mutated B-cell lymphomas.

Cite This Study

Tsakmaklis et al. (2025) studied this question.

synapsesocial.com/papers/69362f694fa91c937236de84https://doi.org/10.1182/blood-2025-2171
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