Correlation of PI3K upregulation with NOTCH2 mutations in ibrutinib-resistant mantle cell lymphoma.

e20065 Background: PI3K dysregulation has been linked to ibrutinib resistance in mantle cell lymphoma (MCL); however, the investigation of PI3K signaling as an important ibrutinib resistance mechanism has been rarely assessed in clinical samples. Therefore, we sought to more fully characterize PI3K dysregulation in ibrutinib-sensitive and -resistant MCL clinical samples at the genomic and transcriptomic levels. Methods: Whole exome sequencing (WES; n = 41) and RNA-seq (n = 93) were performed on fresh peripheral blood, apheresis, or biopsy patient primary samples. All analysis was performed using the BostonGene automated pipeline. Results: To evaluate ibrutinib resistance in MCL, we compared the activity of 11 cellular pathways calculated by PROGENy between ibrutinib-sensitive and -resistant MCL. The PI3K pathway was the most differentially expressed between the two groups (q < 0.005; > 1 median absolute deviation in ibrutinib-resistant MCL). Increased PI3K pathway expression in the ibrutinib-resistant MCL tumors strongly correlated with hyperproliferation (r = 0.49; p = 6e-07). Both hyperproliferation and enriched PI3K expression associated with more frequent NOTCH2 somatic mutations (~22% ibrutinib-resistant MCL with high PI3K expression (p = 0.004) and hyperproliferation (p = 0.003)) that generate a premature stop codon in the PEST domain, likely resulting in hyperactive NOTCH2. Frequent TP53 mutations were identified in ibrutinib-resistant MCL tumors (58%; 3-fold greater vs ibrutinib-sensitive tumors; p = 0.02) based on our cohort and the Agarwal et al., 2019, Nature Medicine cohort. PI3K signaling is a known p53 activator, which may lead to a compensatory tumor suppressive mechanism, indicating that PI3K activation may induce mutational pressure on TP53 to promote MCL survival. VH gene usage variability of the B-cell receptor (BCR), the inducer of PI3K signaling, was not different between ibrutinib-sensitive and -resistant MCL, suggesting that diverse BCR expression does not underlie enriched ibrutinib-resistant MCL PI3K expression. Conclusions: PI3K inhibitors have resulted in underwhelming MCL clinical outcomes; yet, the advent of next-generation PI3K inhibitors such as copanlisib with potentially greater efficacy and less toxicity warrants the continued investigation of PI3K signaling in ibrutinib-resistant MCL. We identified a strong correlation between gain-of-function NOTCH2 mutations and enriched PI3K signaling, suggesting that dual inhibition of NOTCH and PI3K may overcome ibrutinib resistance in MCL.

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Inactivation of RB1 in mantle-cell lymphoma detected by nonsense-mediated mRNA decay pathway inhibition and microarray analysis

Blood ◽

10.1182/blood-2006-11-057208 ◽

2007 ◽

Vol 109 (12) ◽

pp. 5422-5429 ◽

Cited By ~ 56

Author(s):

Magda Pinyol ◽

Silvia Bea ◽

Laura Plà ◽

Vincent Ribrag ◽

Jacques Bosq ◽

...

Keyword(s):

Mantle Cell Lymphoma ◽

Mrna Decay ◽

Chromosomal Abnormalities ◽

Cell Lymphoma ◽

Stop Codon ◽

Premature Stop Codon ◽

Homozygous Deletion ◽

Mantle Cell ◽

Intragenic Deletions ◽

Nonsense Mediated Mrna Decay

Abstract Mantle-cell lymphoma (MCL) is genetically characterized by the translocation t(11;14)(q13;q32) and a high number of secondary chromosomal abnormalities. To identify genes inactivated in this lymphoma, we examined 5 MCL cell lines following a strategy previously described in tumors with microsatellite instability that is based on the combined inhibition of the nonsense-mediated mRNA decay pathway and gene-expression profiling. This approach, together with the design of a conservative algorithm for analysis of the results, allowed the identification of 3 genes carrying premature stop codons. These genes were p53 with a mutation previously described in JEKO-1, the leukocyte-derived arginine aminopeptidase (LRAP) gene in REC-1 that showed a new splicing isoform generating a premature stop codon, and RB1 in UPN-1 that contained an intragenic homozygous deletion resulting in a truncated transcript and total loss of protein expression. The new LRAP isoform was detected also in 2 primary MCLs, whereas inactivating intragenic deletions of RB1 were found in the primary tumor from which UPN-1 was derived and 1 additional blastoid MCL. These tumors carried a concomitant inactivation of p53, whereas p16INK4a was wild type. These results indicate for the first time that RB1 may be inactivated in aggressive MCL by intragenic deletions.

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Transcriptional programming drives Ibrutinib-resistance evolution in mantle cell lymphoma

Cell Reports ◽

10.1016/j.celrep.2021.108870 ◽

2021 ◽

Vol 34 (11) ◽

pp. 108870

Author(s):

Xiaohong Zhao ◽

Michelle Y. Wang ◽

Huijuan Jiang ◽

Tint Lwin ◽

Paul M. Park ◽

...

Keyword(s):

Mantle Cell Lymphoma ◽

Cell Lymphoma ◽

Resistance Evolution ◽

Mantle Cell ◽

Ibrutinib Resistance

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Activation of MYC, a bona fide client of HSP90, contributes to intrinsic ibrutinib resistance in mantle cell lymphoma

Blood Advances ◽

10.1182/bloodadvances.2018016048 ◽

2018 ◽

Vol 2 (16) ◽

pp. 2039-2051 ◽

Cited By ~ 16

Author(s):

Jimmy Lee ◽

Liang Leo Zhang ◽

Wenjun Wu ◽

Hui Guo ◽

Yan Li ◽

...

Keyword(s):

Mantle Cell Lymphoma ◽

Cell Lines ◽

Cell Lymphoma ◽

Resistant Cell ◽

Intrinsic Resistance ◽

Mantle Cell ◽

Myc Gene ◽

Bona Fide ◽

Ibrutinib Resistance ◽

Induced Apoptosis

Abstract The BTK inhibitor ibrutinib has demonstrated a remarkable therapeutic effect in mantle cell lymphoma (MCL). However, approximately one-third of patients do not respond to the drug initially. To identify the mechanisms underlying primary ibrutinib resistance in MCL, we analyzed the transcriptome changes in ibrutinib-sensitive and ibrutinib-resistant cell lines on ibrutinib treatment. We found that MYC gene signature was suppressed by ibrutinib in sensitive but not resistant cell lines. We demonstrated that MYC gene was structurally abnormal and MYC protein was overexpressed in MCL cells. Further, MYC knockdown with RNA interference inhibited cell growth in ibrutinib-sensitive as well as ibrutinib-resistant cells. We explored the possibility of inhibiting MYC through HSP90 inhibition. The chaperon protein is overexpressed in both cell lines and primary MCL cells from the patients. We demonstrated that MYC is a bona fide client of HSP90 in the context of MCL by both immunoprecipitation and chemical precipitation. Furthermore, inhibition of HSP90 using PU-H71 induced apoptosis and caused cell cycle arrest. PU-H71 also demonstrates strong and relatively specific inhibition of the MYC transcriptional program compared with other oncogenic pathways. In a MCL patient-derived xenograft model, the HSP90 inhibitor retards tumor growth and prolongs survival. Last, we showed that PU-H71 induced apoptosis and downregulated MYC protein in MCL cells derived from patients who were clinically resistant to ibrutinib. In conclusion, MYC activity underlies intrinsic resistance to ibrutinib in MCL. As a client protein of HSP90, MYC can be inhibited via PU-H71 to overcome primary ibrutinib resistance.

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HSP90 inhibition overcomes ibrutinib resistance in mantle cell lymphoma

Blood ◽

10.1182/blood-2016-04-711176 ◽

2016 ◽

Vol 128 (21) ◽

pp. 2517-2526 ◽

Cited By ~ 19

Author(s):

Caron Jacobson ◽

Nadja Kopp ◽

Jacob V. Layer ◽

Robert A. Redd ◽

Sebastian Tschuri ◽

...

Keyword(s):

Mantle Cell Lymphoma ◽

Cell Lymphoma ◽

Hsp90 Inhibitors ◽

Hsp90 Inhibition ◽

Key Points ◽

Mantle Cell ◽

Ibrutinib Resistance

Key Points Inhibition of HSP90 targets multiple dependences in mantle cell lymphoma. Clinically available HSP90 inhibitors overcome ibrutinib resistance in vitro and in vivo.

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Anti-Tumor Activity of Single-Agent CCI-779 for Relapsed Mantle Cell Lymphoma: A Phase II Trial in the North Central Cancer Treatment Group.

Blood ◽

10.1182/blood.v104.11.129.129 ◽

2004 ◽

Vol 104 (11) ◽

pp. 129-129 ◽

Cited By ~ 3

Author(s):

Thomas Witzig ◽

Susan Geyer ◽

Irene Ghobrial ◽

David Inwards ◽

Rafael Fonseca ◽

...

Keyword(s):

Cyclin D1 ◽

Mantle Cell Lymphoma ◽

Median Time ◽

Response Rate ◽

Cell Lymphoma ◽

Single Agent ◽

Pi3k Pathway ◽

Mantle Cell ◽

Grade 3 ◽

Anti Tumor Activity

Abstract Purpose: Mantle cell lymphoma (MCL) is characterized by a t(11;14) resulting in overexpression of cyclin D1, a member of the phosphatidylinosital 3 kinase (PI3K) pathway. This study tested whether CCI-779, which inhibits the PI3K pathway at the level of the mammalian target of rapamycin (mTOR) could produce tumor responses in patients (pts) with MCL. Patients and Methods: Eligible pts had biopsy-proven, cyclin D1 positive MCL and had relapsed or were refractory to therapy. Pts received CCI-779 250 mg IV every week as a single agent. Pts were re-staged after 1 cycle (4 doses) and every 3 cycles thereafter. Pts with a tumor response after 6 cycles were eligible to continue drug for a total of 12 cycles or 2 cycles after complete remission (CR) and then were observed. Results: Thirty-five pts were enrolled and evaluable for toxicity; 1 patient had MCL by histology but was cyclin D1 negative and ineligible for efficacy evaluation. The median age was 70 years (range, 38–89), 91% were stage 4, and 69% had ≥ 2 extranodal sites. Pts had received a median of 3 prior therapies (range, 1–11) and 54% were refractory to their last treatment. The overall response rate was 38% (13/34) with 1 CR (3%) and 12 PRs (35%), surpassing the pre-defined criteria for a promising agent. Responses tended to occur rapidly with median time to response of 1 month (range, 1–8). To date, 26 patients have progressed, with a median time-to-progression of 6.8 months (95% CI: 3.8 – 9.7). Median duration of response for the 13 responders was 5.7 months (95% CI: 5.2 – 13.2). Overall, 32 out of 35 patients who received treatment had grade 3 or 4 toxicity. The most common toxicities were hematologic with grade 3 (n=24) or grade 4 (n=4). Thrombocytopenia was the most frequent grade 3/4 toxicity (n=25) and the largest cause of dose-reductions, although counts typically recovered within one week. Only 4 patients could tolerate sustained 250 mg per week throughout their treatment (including one who went on to alternate treatment after 1 cycle) and the median dose/month was 175 mg. Conclusions: Single-agent CCI-779 has substantial anti-tumor activity in relapsed MCL. This study demonstrates that agents, which selectively target cellular pathways dysregulated in MCL cells can produce therapeutic benefit. The high response rate warrants further studies of this agent in MCL, but the high incidence of hematologic toxicity suggests that a lower dose should be explored. CCI-779 at 25mg is currently being evaluated in MCL through an NCCTG trial

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Dual mTORC1/mTORC2 inhibition diminishes Akt activation and induces Puma-dependent apoptosis in lymphoid malignancies

Blood ◽

10.1182/blood-2011-04-346601 ◽

2012 ◽

Vol 119 (2) ◽

pp. 476-487 ◽

Cited By ~ 72

Author(s):

Mamta Gupta ◽

Andrea E. Wahner Hendrickson ◽

Seong Seok Yun ◽

Jing Jing Han ◽

Paula A. Schneider ◽

...

Keyword(s):

Mantle Cell Lymphoma ◽

Cell Lines ◽

Transcriptional Activation ◽

Cell Lymphoma ◽

Lymphocytic Leukemia ◽

Clinical Samples ◽

Lymphoid Malignancies ◽

Mantle Cell ◽

Induced Apoptosis

Abstract The mammalian target of rapamycin (mTOR) plays crucial roles in proliferative and antiapoptotic signaling in lymphoid malignancies. Rapamycin analogs, which are allosteric mTOR complex 1 (mTORC1) inhibitors, are active in mantle cell lymphoma and other lymphoid neoplasms, but responses are usually partial and short-lived. In the present study we compared the effects of rapamycin with the dual mTORC1/mTORC2 inhibitor OSI-027 in cell lines and clinical samples representing divers lymphoid malignancies. In contrast to rapamycin, OSI-027 markedly diminished proliferation and induced apoptosis in a variety of lymphoid cell lines and clinical samples, including specimens of B-cell acute lymphocytic leukemia (ALL), mantle cell lymphoma, marginal zone lymphoma and Sezary syndrome. Additional analysis demonstrated that OSI-027–induced apoptosis depended on transcriptional activation of the PUMA and BIM genes. Overexpression of Bcl-2, which neutralizes Puma and Bim, or loss of procaspase 9 diminished OSI-027–induced apoptosis in vitro. Moreover, OSI-027 inhibited phosphorylation of mTORC1 and mTORC2 substrates, up-regulated Puma, and induced regressions in Jeko xenografts. Collectively, these results not only identify a pathway that is critical for the cytotoxicity of dual mTORC1/mTORC2 inhibitors, but also suggest that simultaneously targeting mTORC1 and mTORC2 might be an effective anti-lymphoma strategy in vivo.

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XPO1 Inhibitor Selinexor Overcomes Intrinsic Ibrutinib Resistance in Mantle Cell Lymphoma via Nuclear Retention of IκB

Molecular Cancer Therapeutics ◽

10.1158/1535-7163.mct-17-0789-atr ◽

2018 ◽

Vol 17 (12) ◽

pp. 2564-2574 ◽

Cited By ~ 13

Author(s):

Mei Ming ◽

Wenjun Wu ◽

Bingqing Xie ◽

Madina Sukhanova ◽

Weige Wang ◽

...

Keyword(s):

Mantle Cell Lymphoma ◽

Cell Lymphoma ◽

Nuclear Retention ◽

Mantle Cell ◽

Ibrutinib Resistance

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Targeting Oxphos Pathway Against Ibrutinib Resistance to Mantle Cell Lymphoma

Blood ◽

10.1182/blood.v128.22.290.290 ◽

2016 ◽

Vol 128 (22) ◽

pp. 290-290 ◽

Cited By ~ 1

Author(s):

Yang Liu ◽

Taylor Bell ◽

Hui Zhang ◽

Yuting Sun ◽

Carrie J Li ◽

...

Keyword(s):

Tumor Growth ◽

Mantle Cell Lymphoma ◽

Cell Lines ◽

Research Funding ◽

Cell Lymphoma ◽

Gene Set Enrichment Analysis ◽

Pdx Model ◽

Mantle Cell ◽

Ibrutinib Resistance

Abstract Background: Mantle cell lymphoma (MCL) is an aggressive B-cell malignancy that is initially responsive but ultimately relapses to frontline therapy. Ibrutinib, a first-in-class, once-daily, oral covalent inhibitor of Bruton's tyrosine kinase (BTK) has achieved 68% of overall response rate in relapsed/refractory mantle cell lymphoma (MCL) patients. However, the vast majority of MCL patients experience disease progression, demonstrating that standard-of-care approaches are failing and that a means for targeting ibrutinib resistant MCL is clinically needed. Our hypothesis is that the ibrutinib-resistant MCL may rely on the mitochondrial oxidative phosphorylation (OXPHOS) pathway to produce energy for tumor growth. In this study, we investigated the effects of IACS-010759, a small molecule mitochondrial complex I inhibitor discovered in MD Anderson Cancer Center which can block the OXPHOS pathway, to overcome ibrutinib resistance in MCL in vitro and in a patient-derived xenograft (PDX) model. Methods: The OXPHOS metabolic pathways were investigated by RNASeq in a panel of ibrutinib-sensitive and -resistant MCL samples. Cell growth inhibition assays were tested after 72-hour treatment with IACS-010759 in ibrutinib-resistant MCL cell lines, Z-138 and Maver-1, and ibrutinib-sensitive MCL cell lines, Rec-1, Mino, and Jeko-1, by CellTiter-Glo luminescent cell viability assay (Promega). Furthermore, an IBN-resistant MCL PDX model was established and the therapeutic effects and tolerability of IACS-010759 were investigated in the primary MCL-bearing PDX model. Results: We have done RNA sequencing (RNASeq) in 7 primary ibrutinib-resistant and 16 ibrutinib-sensitive MCL patient samples, and analyzed the data using Gene Set Enrichment Analysis (GSEA) software. The results demonstrated that the OXPHOS pathway was activated in the primary ibrutinib-resistant MCL cells but not ibrutinib-sensitive MCL cells. Based on the RNASeq data, we selected an OXPHOS inhibitor IACS-010759 to investigate its effects on both primary ibrutinib-resistant and ibrutinib-sensitive MCL cells in vitroand in PDX mice. IACS-010759 significantly inhibited cell proliferation in ibrutinib-resistant MCL cell lines, Z-138 and Maver-1, but not in ibrutinib-sensitive MCL cell lines, Rec-1, Mino, and Jeko-1, during a 72-hour incubation. Furthermore, the primary ibrutinib-resistant MCL PDX mice were administrated with 10 mg/kg IACS-10759 by oral gavage, for 28 days using a 5 on/2 off dosing schedule. Our data showed that IACS-010759 completely eradicated tumor growth in ibrutinib-resistant MCL PDX mice (n=5, p=0.045). All mice tolerated the treatment dose and no toxicity was found during 28 days of IACS-010759 treatment. Conclusions: The OXPHOS inhibitor IACS-010759 overcomes ibrutinib resistance both in vitro and in the PDX mouse model. The investigation of its mechanism-of-action is ongoing. IACS-010759 could have the potential for clinical use in ibrutinib-resistant relapsed/refractory MCL patients. Disclosures Wang: Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Asana BioSciences: Research Funding; Kite Pharma: Research Funding; Juno Therapeutics: Research Funding; Asana biosciences, Beigene, Celgene, Juno, Kite, Onyx, Pharmacyclics: Research Funding; Dava Oncology: Honoraria; BeiGene: Research Funding; Acerta: Consultancy, Research Funding.

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Whole transcriptome sequencing reveals recurrent NOTCH1 mutations in mantle cell lymphoma

Blood ◽

10.1182/blood-2011-11-391474 ◽

2012 ◽

Vol 119 (9) ◽

pp. 1963-1971 ◽

Cited By ~ 222

Author(s):

Robert Kridel ◽

Barbara Meissner ◽

Sanja Rogic ◽

Merrill Boyle ◽

Adele Telenius ◽

...

Keyword(s):

Mantle Cell Lymphoma ◽

Cell Lines ◽

Transcriptome Sequencing ◽

Cell Lymphoma ◽

Notch Pathway ◽

Clinical Samples ◽

Mantle Cell ◽

Whole Transcriptome Sequencing ◽

Whole Transcriptome ◽

Notch1 Mutations

Abstract Mantle cell lymphoma (MCL), an aggressive subtype of non-Hodgkin lymphoma, is characterized by the hallmark translocation t(11;14)(q13;q32) and the resulting overexpression of cyclin D1 (CCND1). Our current knowledge of this disease encompasses frequent secondary cytogenetic aberrations and the recurrent mutation of a handful of genes, such as TP53, ATM, and CCND1. However, these findings insufficiently explain the biologic underpinnings of MCL. Here, we performed whole transcriptome sequencing on a discovery cohort of 18 primary tissue MCL samples and 2 cell lines. We found recurrent mutations in NOTCH1, a finding that we confirmed in an extension cohort of 108 clinical samples and 8 cell lines. In total, 12% of clinical samples and 20% of cell lines harbored somatic NOTCH1 coding sequence mutations that clustered in the PEST domain and predominantly consisted of truncating mutations or small frame-shifting indels. NOTCH1 mutations were associated with poor overall survival (P = .003). Furthermore, we showed that inhibition of the NOTCH pathway reduced proliferation and induced apoptosis in 2 MCL cell lines. In summary, we have identified recurrent NOTCH1 mutations that provide the preclinical rationale for therapeutic inhibition of the NOTCH pathway in a subset of patients with MCL.

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