ERK1/2 pro-survival signalling is suppressed by pirtobrutinib in ibrutinib-resistant MYD88-mutated lymphoma cells

M Munshi; X Liu; A Kofides; N Tsakmaklis; Z R Hunter; M L Guerrera; A Canning; J N Gustine; S Liu; J M Hatcher; J Chen; K Meid; S Sarosiek; C A Flynn; A R Branagan; G von Keudell; L M Palomba; J J Castillo; G Yang; S P Treon

doi:10.1111/bjh.19756

ERK1/2 pro-survival signalling is suppressed by pirtobrutinib in ibrutinib-resistant MYD88-mutated lymphoma cells

Br J Haematol. 2024 Sep 18. doi: 10.1111/bjh.19756. Online ahead of print.

Authors

M Munshi¹, X Liu¹, A Kofides¹, N Tsakmaklis¹, Z R Hunter^{1

2}, M L Guerrera^{1

2}, A Canning¹, J N Gustine^{1

3}, S Liu¹, J M Hatcher¹, J Chen^{1

3}, K Meid¹, S Sarosiek^{1

2}, C A Flynn^{1

2}, A R Branagan^{2

4}, G von Keudell^{2

5}, L M Palomba⁶, J J Castillo^{1

2}, G Yang¹, S P Treon^{1

2}

Affiliations

¹ Dana Farber Cancer Institute, Boston, Massachusetts, USA.
² Harvard Medical School, Boston, Massachusetts, USA.
³ Boston University Medical Center, Boston, Massachusetts, USA.
⁴ Massachusetts General Hospital, Boston, Massachusetts, USA.
⁵ Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA.
⁶ Memorial Sloan Kettering Cancer Center, New York, New York, USA.

PMID: 39295138
DOI: 10.1111/bjh.19756

Abstract

Covalent Bruton's tyrosine kinase-inhibitors (cBTK-i) are highly active in MYD88-mutated (MYD88^Mut) Waldenstrom's macroglobulinaemia and suppress nuclear factor kappa-light-chain-enhancer of activated B cells and extracellular signal-regulated kinases-1/2 (ERK1/2)-related signalling. BTK^Cys481 mutations are associated with cBTK-i acquired resistance and are accompanied by reactivation of ERK1/2 that promotes inflammatory cytokine secretion and paracrine-mediated resistance of BTK wild-type (BTK^WT) tumour cells. Pirtobrutinib is a non-covalent BTK-inhibitor that binds at non-BTK^Cys481 sites. We show that pirtobrutinib blocked p-ERK1/2, ERK1/2-driven inflammatory cytokines, and overcame paracrine-mediated resistance in MYD88^Mut lymphoma cells expressing mutated BTK^Cys481. Our results provide important mechanistic insights for the activity of pirtobrutinib in MYD88^Mut lymphomas carrying BTK^Cys481 mutations.

Keywords: MYD88; ABC DLBCL; BTK; ERK1/2; Waldenstrom's macroglobulinaemia; ibrutinib; pirtobrutinib.

Abstract

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