Cereblon loss and up-regulation of c-Myc are associated with lenalidomide resistance in multiple myeloma patients

Franssen, Laurens E.; Nijhof, Inger S.; Couto, Suzana; Levin, Mark; Bos, Gerard M.J.; Broijl, Annemiek; Klein, Saskia K.; Ren, Yan; Wang, Maria; Koene, Harry R.; Bloem, Andries C.; Beeker, Aart; Faber, Laura M.; Spek, Ellen van der; Raymakers, Reinier; Leguit, Roos J.; Sonneveld, Pieter; Zweegman, Sonja; Lokhorst, Henk M.; Mutis, Tuna; Thakurta, Anjan; Qian, Xiaozhong; Donk, Niels W.C.J. van de

doi:10.3324/haematol.2017.186601

Cited by 50 publications

(44 citation statements)

References 13 publications

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“…Ikaros/Aiolos. Previous studies have shown that dysregulation of the IRF4/MYC pathways is associated with lenalidomide resistance [21][22][23][24], supporting our findings. Our data suggest that MYC expression at baseline could predict longterm PCD efficacy and should be taken into consideration when planning future treatment protocols.…”

Section: Discussionsupporting

confidence: 91%

A phase II study of pomalidomide, daily oral cyclophosphamide, and dexamethasone in relapsed/refractory multiple myeloma

Oekelen

Parekh

Cho

et al. 2020

Leukemia & Lymphoma

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Relapsed/refractory multiple myeloma patients treated with pomalidomide and dexamethasone have an overall response rate (ORR) of $30% and median progression-free survival (PFS) of 4-5 months. Previous studies explored addition of weekly cyclophosphamide, but we hypothesized that daily dosing allows for better synergy. We report the open-label, single-center phase II study of pomalidomide, daily cyclophosphamide and weekly dexamethasone (PCD). Thirtythree patients were evaluable for efficacy and underwent 28-day cycles of pomalidomide (4 mg/ day, D1-21), cyclophosphamide (50 mg b.i.d., D1-21) and weekly dexamethasone. All were lenalidomide-refractory and 55% were refractory to lenalidomide and proteasome inhibitor. ORR was 73%; median PFS and overall survival were 13.3 months and 57.2 months respectively. Grade 3/4 toxicities were primarily hematologic but manageable with dose reductions. Early disease progression correlated with MYC expression and flow cytometry demonstrates an activated microenvironment post-PCD. Addition of metronomic cyclophosphamide to pomalidomide and dexamethasone is a cost-effective, oral regimen with encouraging PFS.

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Section: Discussionsupporting

confidence: 91%

A phase II study of pomalidomide, daily oral cyclophosphamide, and dexamethasone in relapsed/refractory multiple myeloma

Oekelen

Parekh

Cho

et al. 2020

Leukemia & Lymphoma

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“…Notably, the 1LoT‐SCT subgroup appeared to have the longest PFS with placebo‐Rd, independent of c‐MYC expression, suggesting that the greater PFS benefit with IRd vs placebo‐Rd in TOURMALINE‐MM1 in 1LoT‐noSCT and 2/3LoT patients might have been driven by reduced activity of placebo‐Rd in these subgroups. This finding is supported by a recent report suggesting high c‐MYC expression as a potential mechanism of resistance to lenalidomide activity in MM …”

Section: Discussionsupporting

confidence: 86%

c‐MYC expression and maturity phenotypes are associated with outcome benefit from addition of ixazomib to lenalidomide‐dexamethasone in myeloma

Bacco

Bahlis

Munshi

et al. 2020

European J of Haematology

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Objectives In the TOURMALINE‐MM1 phase 3 trial in relapsed/refractory multiple myeloma, ixazomib‐lenalidomide‐dexamethasone (IRd) showed different magnitudes of progression‐free survival (PFS) benefit vs placebo‐Rd according to number and type of prior therapies, with greater benefit seen in patients with >1 prior line of therapy or 1 prior line of therapy without stem cell transplantation (SCT). Methods RNA sequencing data were used to investigate the basis of these differences. Results The PFS benefit of IRd vs placebo‐Rd was greater in patients with tumors expressing high c‐MYC levels (median not reached vs 11.3 months; hazard ratio [HR] 0.42; 95% CI, 0.26, 0.66; P < .001) compared with in those expressing low c‐MYC levels (median 20.6 vs 16.6 months; HR 0.75; 95% CI, 0.42, 1.2). Expression of c‐MYC in tumors varied based on the number and type of prior therapy received, with the lowest levels observed in tumors of patients who had received 1 prior line of therapy including SCT. These tumors also had higher expression levels of CD19 and CD81. Conclusions PFS analyses suggest that lenalidomide and ixazomib target tumors with different levels of c‐MYC, CD19, and CD81 expression, thus providing a potential rationale for the differential benefits observed in the TOURMALINE‐MM1 study. This trial was registered at http://www.clinicaltrials.gov as: NCT01564537

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“…Decreased expression or mutation of the components of the CRL4 CRBN complex have been proposed to mediate resistance, but this explains only a fraction of resistant cases, and other resistance mechanisms are likely to exist. [11][12][13] Further study of these questions has been made difficult by the technical challenges associated with quantitative protein measurement of both CRBN and its substrates. We developed and used a quantitative mass spectrometry (MS)-based assay to measure CRBN, thalidomide analog, and protein substrates to characterize the activity of thalidomide analogs and identify novel modes of drug resistance.…”

Section: Introductionmentioning

confidence: 99%

Patterns of substrate affinity, competition, and degradation kinetics underlie biological activity of thalidomide analogs

Sperling

Burgess

Keshishian

et al. 2019

Blood

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Pharmacologic agents that modulate ubiquitin ligase activity to induce protein degradation are a major new class of therapeutic agents, active in a number of hematologic malignancies. However, we currently have a limited understanding of the determinants of activity of these agents and how resistance develops. We developed and used a novel quantitative, targeted mass spectrometry (MS) assay to determine the relative activities, kinetics, and cell-type specificity of thalidomide and 4 analogs, all but 1 of which are in clinical use or clinical trials for hematologic malignancies. Thalidomide analogs bind the CRL4CRBN ubiquitin ligase and induce degradation of particular proteins, but each of the molecules studied has distinct patterns of substrate specificity that likely underlie the clinical activity and toxicities of each drug. Our results demonstrate that the activity of molecules that induce protein degradation depends on the strength of ligase-substrate interaction in the presence of drug, the levels of the ubiquitin ligase, and the expression level of competing substrates. These findings highlight a novel mechanism of resistance to this class of drugs mediated by competition between substrates for access to a limiting pool of the ubiquitin ligase. We demonstrate that increased expression of a nonessential substrate can lead to decreased degradation of other substrates that are critical for antineoplastic activity of the drug, resulting in drug resistance. These studies provide general rules that govern drug-dependent substrate degradation and key differences between thalidomide analog activity in vitro and in vivo.

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Cereblon loss and up-regulation of c-Myc are associated with lenalidomide resistance in multiple myeloma patients

Cited by 50 publications

References 13 publications

A phase II study of pomalidomide, daily oral cyclophosphamide, and dexamethasone in relapsed/refractory multiple myeloma

A phase II study of pomalidomide, daily oral cyclophosphamide, and dexamethasone in relapsed/refractory multiple myeloma

c‐MYC expression and maturity phenotypes are associated with outcome benefit from addition of ixazomib to lenalidomide‐dexamethasone in myeloma

Patterns of substrate affinity, competition, and degradation kinetics underlie biological activity of thalidomide analogs

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