SWI/SNF Mutations Confer Resistance to Ibrutinib plus Venetoclax in MCL

Mantle cell lymphoma (MCL) is a B-cell malignancy that is generally refractory to conventional chemotherapy, but a recent phase II study showed that combined targeting of constitutive B-cell receptor signaling with the Bruton tyrosine kinase (BTK) inhibitor ibrutinib and antiapoptotic signaling with the BCL2 inhibitor venetoclax leads to complete responses in approximately 70% of patients with relapsed or refractory MCL. However, 20% of patients were intrinsically resistant to this regimen and an additional 10% of patients relapsed following an initial response. Agarwal, Chan, and colleagues sought to evaluate the genomic determinants of response and resistance to ibrutinib plus venetoclax in patients enrolled in this trial as well as to establish improved methods to monitor these genomic features in the clinic with the ultimate goal of predicting response or emerging resistance. Whole-exome sequencing of the 24 patients enrolled in the trial revealed that the 5 nonresponders each harbored mutations or chromosomal losses affecting genes encoding subunits of the SWI/SNF chromatin remodeling complex. Knockdown of the SWI/SNF ATPase SMARCA4 in MCL cells conferred resistance to combined ibrutinib plus venetoclax and was associated with reduced chromatin accessibility and expression of the transcription factor gene ATF3, which resulted in increased expression of the ATF3 antiapoptotic target gene BCL-xL to confer resistance to the combination of ibrutinib and venetoclax. Of note, inhibition of BCL-xL restored sensitivity to ibrutinib and venetoclax in MCL cells. These genomic alterations were monitorable in real time through detection of circulating tumor DNA (ctDNA) levels, and patients with detectable SWI/SNF gene mutations and/or loss of chromosome 9p21.1-24.3 (harboring the other SWI/SNF ATPase gene, SMARCA2) had significantly shorter progression-free survival. Intrinsic and secondary resistance could also be tracked longitudinally by monitoring ctDNA levels. These findings provide initial insight into mechanisms underlying resistance to combined BTK and BCL2 inhibition and show the feasibility of monitoring response to MCL therapy with ctDNA testing.

Agarwal R, Chan YC, Tam CS, Hunter T, Vassiliadis D, Teh CE, et al. Dynamic molecular monitoring reveals that SWI-SNF mutations mediate resistance to ibrutinib plus venetoclax in mantle cell lymphoma. Nat Med 2018 Nov 19 [Epub ahead of print].

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