Cell-Cycle Reprogramming for PI3K Inhibition Overrides a Relapse-Specific C481SBTKMutation Revealed by Longitudinal Functional Genomics in Mantle Cell Lymphoma

Abstract

Despite the unprecedented clinical activity of the Bruton’s tyrosine kinase inhibitor ibrutinib in MCL, acquired-resistance is common. By longitudinal integrative whole-exome and whole-transcriptome sequencing and targeted sequencing, we identified the first relapse-specific C481S mutation at the ibrutinib-binding site of BTK in MCL cells at progression following a durable response. This mutation enhanced BTK and AKT activation and tissue-specific proliferation of resistant MCL cells driven by CDK4 activation. It was absent, however, in patients with primary-resistance or progression following transient response to ibrutinib, suggesting alternative mechanisms of resistance. Through synergistic induction of PIK3IP1 and inhibition of PI3K-AKT activation, prolonged early G1 arrest induced by PD 0332991 (palbociclib) inhibition of CDK4 sensitized resistant lymphoma cells to ibrutinib killing when BTK was unmutated, and to PI3K inhibitors independent of C481S mutation. These data identify a genomic basis for acquired-ibrutinib resistance in MCL and suggest a strategy to override both primary- and acquired-ibrutinib resistance.

Acquired mutations associated with ibrutinib resistance in Waldenström macroglobulinemia

“…[14][15][16][17] We therefore examined sorted lymphoplasmacytic cells from WM patients with progressive disease on ibrutinib, on ibrutinib without clinical progression at time of bone marrow (BM) sampling, as well as untreated and previously treated ibrutinib-naïve patients, for mutations known to be associated with ibrutinib progression. For these efforts, we used Sanger, as well as cloning and sequencing studies to identify BTK Cys481 mutations associated with clinical progression in WM, and developed highly sensitive and allele-specific polymerase chain reaction (AS-PCR) assays for their detection to perform screening.…”

Postibrutinib outcomes in patients with mantle cell lymphoma

“…Although mutations in the BTK binding site have been identified, the mechanisms of ibrutinib resistance remain unclear and are likely multiple. [4][5][6] After several investigators from early trials noted the challenges associated with treating patients with ibrutinib-resistant MCL, an observation also reported in CLL, 7 we performed a large, international, retrospective cohort study of all patients with MCL that experienced disease progression while receiving ibrutinib across 15 international sites. The aim of the study was to improve our understanding of patient outcomes and potentially to identify risk factors associated with survival.…”

Crosstalk between ROR1 and BCR pathways defines novel treatment strategies in mantle cell lymphoma

“…3 Despite an initial 70% response rate of MCL patients to ibrutinib monotherapy, primary or acquired ibrutinib resistance remains a challenge. [4][5][6] BCR-mediated NF-kB activation regulates MCL cell survival and involves the canonical NF-kB pathway, linking the cytoplasmic-signaling cascade of IkB kinases to the intermediate caspase recruitment domain-containing protein 11 (CARD11), mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1), and B-cell lymphoma/leukemia 10 (BCL10) signaling complex, resulting in phosphorylation of IkBa and nuclear translocation of heterodimeric p50/p65 NF-kB transcription factors. The alternative NF-kB pathway is regulated mainly through the control of NF-kB-inducing kinase (NIK) and p52 turnover, with tumor necrosis factor (TNF) receptorassociated factor 3 (TRAF3), TRAF2, and cellular inhibitor of apoptosis 1/2 (cIAP1/2) critically involved in this process.…”