Inhibition of MAPK-ERK Signaling Pathway Overcomes Microrna-Mediated Ibrutinib Resistance in Mantle Cell Lymphoma

Kersy, Olga; Salmon‐Divon, Mali; Silva, Maria Gomes da; Moita, Ana Filipa; Cabeçadas, José; Klener, P; Trněný, Marek; Basood, May; Shpilberg, Ofer; Hershkovitz‐Rokah, Oshrat

doi:10.1182/blood-2022-169574

Cited by 3 publications

(3 citation statements)

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“…In addition, when we consider an entire pathway, mutations in MAPK related genes, BRAF, NRAS, KRAS, and MAP2K1, were enriched in the PD group and had signi cantly higher VAFs. Previous reports have demonstrated that CD79B overexpression activated MAPK leading to IBR resistance in ABC-diffuse large B cell lymphoma and MAPK-ERK inhibition was effective in IBR resistant mantle cell lymphoma [32,33]. MAPK pathway activation could potentially bypass BTK inhibition and allow CLL cells to proliferate.…”

Section: Discussionmentioning

confidence: 99%

Mutations Detected in Real World Clinical Sequencing during BTK Inhibitor Treatment in CLL

Brown,

Mashima,

Fernandes

et al. 2024

Preprint

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We retrospectively analyzed 609 chronic lymphocytic leukemia (CLL) patients treated with BTK inhibitors (BTKis) at Dana-Farber Cancer Institute from 2014 to 2022. Among them, 85 underwent next-generation sequencing (NGS) during or after BTKi therapy (ibrutinib, 64; acalabrutinib, 13; pirtobrutinib, 7; vecabrutinib, 1). Patients with NGS at progression (N=36, PD group) showed more 17p deletion, complex karyotype, and previous treatments including BTKi, compared to ongoing responders (N=49, NP group). 216 variants were found in 57 genes across both groups, with more variants in the PD group (158 variants, 70.3% pathogenic, P<0.001). The PD group had a higher incidence of pathogenic variants (70.3%, P<0.001), including 32 BTK (BTK C481S/F/R/Y, L528W, and T474I/L) and 4 PLCG2mutations. Notably, a high VAF L528W mutation was found in a first line ibrutinib-resistant patient. TP53, SF3B1, and NOTCH2mutations were also significantly more prevalent in the PD group (P<0.01, P<0.05, P<0.05). Additionally, MAPK pathway gene mutations trended more common and had higher VAFs in the PD group (P=0.041). T474 mutations were found in 4 of 6 patients progressing on pirtobrutinib, and BTK L528W mutation can arise with both covalent and non-covalent BTKi therapy. These results also suggest that RAS/RAF/MAPK pathway mutations may contribute to BTKi resistance.

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Section: Discussionmentioning

confidence: 99%

Mutations Detected in Real World Clinical Sequencing during BTK Inhibitor Treatment in CLL

Brown,

Mashima,

Fernandes

et al. 2024

Preprint

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“…Additionally, as seen in cBTKi resistance, alternative While the exact signaling mechanism of resistance in these inactivating ncBTKi mutations requires further study, recent articles have reported a noncatalytic scaffolding function of BTK with HCK or LYN or dependencies of kinase-deficient BTK mutants on TLR9, UNC93B1, CNPY3 [48][49][50][51]. Additionally, as seen in cBTKi resistance, alternative receptor tyrosine kinase (RTK) signaling through such pathways as the RAS-MAP kinase, NFkB, or PI3K-mTOR can also contribute to resistance through complementary survival signaling [46,[52][53][54][55].…”

Section: Mechanisms Of Resistance To Non-covalent Btk Inhibitorsmentioning

confidence: 99%

Non-Covalent Bruton’s Tyrosine Kinase Inhibitors in the Treatment of Chronic Lymphocytic Leukemia

Montoya

Thompson

2023

Cancers

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Covalent Bruton’s tyrosine kinase inhibitors (cBTKi) have led to a paradigm shift in the treatment of chronic lymphocytic leukemia (CLL). These targeted oral therapies are administered as standard treatments in both the front-line and relapsed and/or refractory settings. Given their administration as a continuous therapy with a “treat-to-progression” strategy, limitations of their use include discontinuation due to toxicity or from progression of the disease. Non-covalent Bruton’s tyrosine kinase inhibitors (ncBTKi) distinguish themselves by binding reversibly to the BTK target, which may address the limitations of toxicity and acquired resistance seen with cBTKi. Several ncBTKis have been studied preclinically and in clinical trials, including pirtobrutinib and nemtabrutinib. Pirtobrutinib, which is now FDA approved for relapsed and/or refractory mantle cell lymphoma (MCL), has shown outstanding safety and preliminary efficacy in CLL in phase 1 and 2 clinical trials, with phase 3 trials underway. This agent may fill an unmet medical need for CLL patients requiring treatment after a cBTKi. Pirtobrutinib is particularly promising for the treatment of “double exposed” CLL, defined as CLL requiring treatment after both a cBTKi and venetoclax. Some patients have now developedacquired resistance to pirtobrutinib, and resistance mechanisms (including novel acquired mutations in BTK outside of the C481 position) have been recently described. Further study regarding the mechanisms of resistance to pirtobrutinib in patients without prior cBTKi exposure, as well as the potential for cross-resistance between cBTKi and ncBTKis, may be important to help inform where ncBTKis will ultimately fit in the treatment sequencing paradigm for CLL. An emerging clinical challenge is the treatment of CLL after ncBTKi discontinuation. Novel therapeutic strategies are being investigated to address the treatment of patients following disease progression on ncBTKis. Such strategies include novel agents (BTK degraders, bispecific antibody therapy, CAR T-cell therapy, PKC-beta inhibitors) as well as combination approaches incorporating a ncBTKi (e.g., pirtobrutinib and venetoclax) that may help overcome this acquired resistance.

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“…Identifying alternative oncogenic pathways in BTKi-resistant MCL has been limited to protein-coding genes. However, one study identified subsets of miRNAs that regulate the MAPK-ERK cascade, including miRs-221, 146a, 182, 342, and the let-7 family members were downregulated in ibrutinib-resistant MCL cells, thereby causing upregulation of MAPK-ERK signaling which can be targetable by MEK inhibitor (cobimetinib) [ 150 ].…”

Section: Other Therapeutic Agents In MCLmentioning

confidence: 99%

Beyond Bruton’s tyrosine kinase inhibitors in mantle cell lymphoma: bispecific antibodies, antibody–drug conjugates, CAR T-cells, and novel agents

Jain,

Mamgain,

Chowdhury

et al. 2023

J Hematol Oncol

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Mantle cell lymphoma is a B cell non-Hodgkin lymphoma (NHL), representing 2–6% of all NHLs and characterized by overexpression of cyclin D1. The last decade has seen the development of many novel treatment approaches in MCL, most notably the class of Bruton's tyrosine kinase inhibitors (BTKi). BTKi has shown excellent outcomes for patients with relapsed or refractory MCL and is now being studied in the first-line setting. However, patients eventually progress on BTKi due to the development of resistance. Additionally, there is an alteration in the tumor microenvironment in these patients with varying biological and therapeutic implications. Hence, it is necessary to explore novel therapeutic strategies that can be effective in those who progressed on BTKi or potentially circumvent resistance. In this review, we provide a brief overview of BTKi, then discuss the various mechanisms of BTK resistance including the role of genetic alteration, cancer stem cells, tumor microenvironment, and adaptive reprogramming bypassing the effect of BTK inhibition, and then provide a comprehensive review of current and emerging therapeutic options beyond BTKi including novel agents, CAR T cells, bispecific antibodies, and antibody–drug conjugates.

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Inhibition of MAPK-ERK Signaling Pathway Overcomes Microrna-Mediated Ibrutinib Resistance in Mantle Cell Lymphoma

Cited by 3 publications

References 0 publications

Mutations Detected in Real World Clinical Sequencing during BTK Inhibitor Treatment in CLL

Mutations Detected in Real World Clinical Sequencing during BTK Inhibitor Treatment in CLL

Non-Covalent Bruton’s Tyrosine Kinase Inhibitors in the Treatment of Chronic Lymphocytic Leukemia

Beyond Bruton’s tyrosine kinase inhibitors in mantle cell lymphoma: bispecific antibodies, antibody–drug conjugates, CAR T-cells, and novel agents

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