Functional characterization of BTKC481S mutation that confers ibrutinib resistance: exploration of alternative kinase inhibitors

Cheng, Shuhua; A, Guo; Lü, Ping; Ma, Jiao; Coleman, Morton; Wang, Y. Lynn

doi:10.1038/leu.2014.263

Cited by 139 publications

(140 citation statements)

References 23 publications

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“…Although BTK and PLCG2 mutations are the predominant mechanisms responsible for ibrutinib resistance, 16,17,37 patient cases lacking these mutations have been reported. 18 To identify alternative resistance mechanisms that might drive disease progression, we compared genetic abnormalities of the CLL relapse PB/BM samples with paired preibrutinib PB/BM samples in each of the 9 patients (shown in Figure 3A-B).…”

Section: Recurrent Abnormalities At Relapse Versus Pretreatmentmentioning

confidence: 99%

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Clonal evolution underlying leukemia progression and Richter transformation in patients with ibrutinib-relapsed CLL

Kadri¹,

Lee²,

Fitzpatrick³

et al. 2017

Blood Advances

109

138

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Key Points• Del(18p), together with del(17p)/TP53 mutations, is present at a high frequency before ibrutinib treatment.• BTK mutations drive ibrutinib relapse, but del(17p)/TP53 mutations may be dispensable.Ibrutinib has generated remarkable responses in patients with chronic lymphocytic leukemia (CLL), including those with an unfavorable cytogenetic profile. However, patients develop resistance, with poor outcomes and no established treatment options. Mutations in BTK and PLCG2 have emerged as main mechanisms of drug resistance, but not all patients carry these mutations. Further understanding of mechanisms of resistance is urgently needed and will support rational development of new therapeutic strategies. To that end, we characterized the genomic profiles of serial samples from 9 patients with ibrutinib-relapsed disease, including 6 who had Richter transformation. Mutations, indels, copy-number aberrations, and loss of heterozygosity were assessed using next-generation sequencing and single-nucleotide polymorphism array. We found that 18p deletion (del(18p)), together with del(17p)/TP53 mutations, was present in 5 of 9 patients before ibrutinib therapy. In addition to BTK C481 , we identified BTK T316A, a structurally novel mutation located in the SH2 domain of BTK. Minor BTK clones with low allele frequencies were captured in addition to major BTK clones. Although TP53 loss predisposes patients for relapse, clone size of TP53 loss may diminish during disease progression while mutant BTK clone expands. In patients who had Richter transformation, we found that the transformed cells were clonal descendants of circulating leukemia cells but continued to undergo evolution and drifts.Surprisingly, transformed lymphoma cells in tissue may acquire a different BTK mutation from that in the CLL leukemia cells. Collectively, these results provide insights into clonal evolution underlying ibrutinib relapse and prompt further investigation on genomic abnormalities that have clinical application potential.

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Section: Recurrent Abnormalities At Relapse Versus Pretreatmentmentioning

confidence: 99%

“…Pre (35) Pre (28) Pre (38) Rel (36) Rel (46) Rel (39) Pre (23) Pre (24) Pre (29) Rel (29) Rel (27) Rel (29) Pre(19) Pre(34) Pre (37) Rel ( (Table 2 also lists emerging minor clones). LOH, loss of heterozygosity.…”

Section: Cll021 Cll024mentioning

confidence: 99%

Clonal evolution underlying leukemia progression and Richter transformation in patients with ibrutinib-relapsed CLL

Kadri¹,

Lee²,

Fitzpatrick³

et al. 2017

Blood Advances

109

138

View full text Add to dashboard Cite

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“…15,18 The mutations identified in PLCG2 have all been demonstrated to be potentially gain-of-function, allowing activation through the BCR even in the presence of inactive BTK. 15,19 Mutations in BTK and/or PLCG2 are present in 85% to 90% of patients at relapse when using highsensitivity assays.…”

Section: Epidemiology and Natural History Of Ibrutinib Resistance In Cllmentioning

confidence: 99%

How I manage ibrutinib-refractory chronic lymphocytic leukemia

Woyach

2017

Blood

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The introduction of the Bruton tyrosine kinase (BTK) inhibitor ibrutinib has dramatically changed the management of chronic lymphocytic leukemia (CLL). Although responses have been durable in the majority of patients, relapses do occur, especially in the high-risk patient population. Most relapses occur as the result of acquired mutations in BTK and PLCG2, which may facilitate success with alternative targeted therapies. As outcomes after ibrutinib relapse have been reported to be poor, specific strategies are needed for this patient population. Here, I discuss the diagnosis and management of ibrutinib-refractory CLL. The focus will be on common clinical scenarios that can be mistaken for relapse and how to accurately determine which patients are relapsing. Because there is no established standard of care, I discuss currently available options for standard therapy and existing clinical data. I also discuss new agents with the potential to be effective in patients refractory to ibrutinib. Finally, I discuss strategies for long-term disease control in this patient population.

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“…16 mTORC1 (Raptor) is activated by AKT and leads to phosphorylation of downstream effectors, which include 4EBP1 and S6, 12,17 whereas mTORC2 (Rictor) phosphorylates AKT at the serine residue 473, leading to AKT activation. 16,18 In healthy B cells, mTORC1 and mTORC2 are both critical for proliferation and differentiation through distinct mechanisms.…”

Section: Introductionmentioning

confidence: 99%

“…Indeed, acquired resistance to ibrutinib was reported in patients due to mutations in BTK or in downstream kinases. 11,12 Drugs that target both BCR signaling and critical survival pathways could provide an improved therapeutic strategy for CLL.…”

Section: Introductionmentioning

confidence: 99%

Dual TORK/DNA-PK inhibition blocks critical signaling pathways in chronic lymphocytic leukemia

Thijssen

Burg

Garrick³

et al. 2016

Blood

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Functional characterization of BTKC481S mutation that confers ibrutinib resistance: exploration of alternative kinase inhibitors

Cited by 139 publications

References 23 publications

Clonal evolution underlying leukemia progression and Richter transformation in patients with ibrutinib-relapsed CLL

Clonal evolution underlying leukemia progression and Richter transformation in patients with ibrutinib-relapsed CLL

How I manage ibrutinib-refractory chronic lymphocytic leukemia

Dual TORK/DNA-PK inhibition blocks critical signaling pathways in chronic lymphocytic leukemia

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