MCL-1 Dependency As a Novel Vulnerability for Aggressive B Cell Lymphomas Michelle Y

Wang et al. Blood Cancer Journal (2021) 11:14 https://doi.org/10.1038/s41408-020-00402-2 Blood Cancer Journal

CORRESPONDENCE Open Access MCL-1 dependency as a novel vulnerability for aggressive B cell lymphomas Michelle Y. Wang1, Tao Li1,YuanRen1,BijalD.Shah2,TintLwin1,JingGao1,KennethH.Shain1,2,3,WeiZhang4, Xiaohong Zhao 1 and Jianguo Tao 1,5

Dear Editor, lymphoma therapy or upon emergence of tumor resis- Mantle cell lymphoma (MCL) and diffuse large B cell tance characterized by upregulation of MCL-1. lymphoma (DLBCL) are aggressive hematologic malig- Here, we exploited the MCL-1 dependency in MCL and nancies characterized by the accumulation of lymphoid DLBCL by implementing pharmacogenomic and chemical cells defective in cell apoptosis biology and function1. The proteomic approaches5,7 to investigate the molecular drug anti-apoptotic B cell lymphoma 2 (BCL-2) family proteins response and resistance mechanism to MCL-1 inhibitors. are pivotal regulators of the mitochondrial apoptotic We demonstrated that transcriptome and kinome repro- pathway and genetic aberrations in these genes are asso- graming linked to the MEK and ERK pathways contribute ciated with lymphomagenesis and chemotherapeutic to MCL-1 inhibitor resistance via regulation of the BCL-2 resistance. These anti-apoptotic proteins, most notably family proﬁle. Further analysis revealed synergistic activity BCL-2 and myeloid cell leukemia 1 (MCL-1), promote the of MCL-1 inhibitors in combinations with inhibitors of survival of lymphoma cells by counteracting the activity of MEK, ERK, and BCR in MCL-1 inhibitor-resistant MCL/ pro-apoptotic proteins such as BCL-2-like protein 11 DLBCL lines and primary samples. These results provide – (BCL2L11, also known as BIM)2 4. Pharmacological tar- a strong rationale for further evaluation of MCL-1 inhi-

1234567890():,; 1234567890():,; 1234567890():,; 1234567890():,; geting of BCL-2 is highly effective in certain B cell lym- bitor in combination with established therapy in the phomas, but de novo and acquired resistance to BCL-2 clinical setting and highlight a potential strategy for inhibitor monotherapy often develop, especially in overcoming MCL-1 inhibitor resistance. aggressive B cell lymphomas. Moreover, the other major First, we affirmed the dependency of MCL-1 in MCL anti-apoptotic BCL-2 family proteins, BCL-XL and MCL- and DLBCL survival and growth. We performed cell- 1, are demonstrated to be the main determinants of viability assays in a panel of MCL and DLBCL lines for resistance to venetoclax5. Additionally, MCL-1 is recur- their susceptibility to specific MCL-1 inhibitor, S63845. rently highly expressed in various kinds of non-Hodgkin’s As shown in Fig. 1A, most MCL and DLBCL lines were B cell lymphomas6. Collectively, these data support the highly sensitive to S63845. Additionally, MCL-1 inhibition hypothesis that MCL-1 plays a central role in B cell with S63845 triggered dramatic PARP cleavage in MCL/ lymphoma progression and drug resistance. Pharmaco- DLBCL lines and primary samples, indicating that the logically targeting MCL-1, therefore, represents an compound’s inhibitory effect was attributed to induced attractive strategy to combat these lymphomas. To this mitochondrial-mediated apoptosis (Fig. S1A). These end, there is a great need to develop and apply selective results are in line with the notion that MCL and DLBCL small-molecule MCL-1 inhibitors as part of a first-line typically have high expression of MCL-1 as well as BCL-2 (refs. 6,8). While targeting MCL-1 appears to be a viable therapeutic strategy9, previous clinical and pre-clinical fi Correspondence: Xiaohong Zhao (Xiaohong.Zhao@mof tt.org)or data suggest that treatment with single-agent anti-BCL-2 Jianguo Tao (Jianguo.Tao@moffitt.org) 1Chemical Biology and Molecular Medicine Program, H. Lee Moffitt Cancer family member therapy is associated with the rapid Center & Research Institute, Tampa, FL 33612, USA acquisition of resistance. 2 fi Department of Malignant Hematology, H. Lee Mof tt Cancer Center & In anticipation of the evolution of MCL-1 inhibitor Research Institute, Tampa, FL 33612, USA Full list of author information is available at the end of the article resistance, we developed MCL-1 resistance (MR) models These authors contributed equally: Michelle Y. Wang, Tao Li

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A C Mino MR 150 MCL 100 JVM-2 100 gGFP gBCL-2 Maver-1

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e 100 R SP53 BCL-2 Z138C 50 0 0.0001 0.001 0.01 0.1 1 10 β-Actin DLBCL 0 0050 100 15 Karpas-422 Time (h) 100 OCI-LY3 gGFP_S63845 gBCL-2_S63845 OCI-LY10 Toldeo HBL-1 HT 50 OCI-LY7 OCI-LY19 D NES = 1.917 Relative Cell Viability (%) Relative Cell Viability Pfeiffer 0.5 0.4 FDRq = 0.004 SUDHL-6 0.3 0.2 KEGG_B_Cell_Receptor SUDHL-10 0 0.1 Signaling_Pathway 0.0001 0.001 0.01 0.1 1 10 SUDHL-16 0.0 [S63845], μM TMD8

HBL-2 SUDHL-16 Maver-1 Mino MCL-0448 B 0.4 NES = 1.520 0.3 FDRq = 0.041 PPPMR MR MR P MR P MR 0.2 BCL-2 0.1 0.0 MEK_UP.V1_UP 1.00 2.18 1.00 1.85 1.00 1.54 1.00 1.41 1.00 1.41 -0.1

β-Actin Enrichment Score (ES)

NES = 1.696 E FGFR1 0.4 0.3 FDRq = 0.011 MLKL3 0.2 TK FYN 0.1 MTOR_UP.V1_UP JAK3 TKL 0.0 LCK DLK -0.1 TEC BRAF FAK STE BTK Resistant Parental TAK1 MST2 MST1 MAP3K1 HPK1 GCK KHS2 COT CMGC MAP2K7 TAO1 MAP2K1 GSK3B CK2a1 MAP2K3 GSK3A CK1 F HBL-2 SUDHL-16 Maver-1 Mino Erk2 JNK1 IKKb PPPMR MR MR P MR CDK4 CDK6 RSK1 PDK1 p70S6K RSK4 AKT1 CDK2 PKN2 BIM PKCd Atypical Protein Kinases ABC1 PKACb AGC 1.00 0.56 1.00 1.01 1.00 0.78 0.00 0.00 Alpha MAPKAPK3 CaMK2g Brd p-ERK 1/2 PDHK 1.00 1.54 1.00 1.65 1.00 5.10 1.00 2.17 PIKK CAMK RIO t-ERK 1/2 TIF1 Specific to MAPK Pathway 1.00 0.93 1.00 1.07 1.00 0.95 1.00 0.78 Specific to mTOR Pathway Specific to BCR Pathway β-Actin Common to multiple pathways Upregulated Kinases

Fig. 1 (See legend on next page.)

by treating S63845-sensitive cell lines with high doses of IC50s for S63845 were more than 10–100-fold higher in all S63845 for an extended period in MCL, DLBCL, and derived resistant lines (Fig. S1B). Similarly, these MR MCL-derived lines (10 × IC50 for 3 months). Though lines showed a comparable level of resistance to the parental lines were exquisitely sensitive to S63845, the chemically distinct MCL-1 inhibitor, AZD5991 (Fig. S1C).

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(see figure on previous page) Fig. 1 MCL-1 dependency and development of resistance to MCL-1 inhibition in mantle cell lymphoma (MCL) and diffuse large B cell lymphoma (DLBCL). A Dose–response curves of MCL (top) and DLBCL (bottom) cell lines treated with S63845 for 72 h. Data are shown as mean ± SD, n = 3 technical replicates for each cell line. B Western blot analysis of BCL-2 protein expression in paired parental (P) and S63845-resistant (MR) cell lines. Band density was quantified and each MR cell line was normalized to its parental cell line. C Image-based cell-viability assays of MR cells with and without BCL-2 knockdown in response to S63845 (top: 10 μM, bottom: 1.11 μM). Inset: western blot confirming BCL-2 knockdown in each MR cell line. D Gene set enrichment analysis (GSEA) enrichment score plots of selected pathways from KEGG (C2) and Oncogenic Signatures (C6) gene sets from MSigDB. Genes were ranked according to their gene expression fold change between SUDHL-16 MR and parental cells. NES normalized enrichment score, FDRq false discovery rate adjusted p value. E Kinome tree representation of kinases with activity significantly upregulated in SUDHL-16 MR cells compared to parental cells. Upregulated kinases defined as having fold change of 1.5. Labeled kinases belong to the BCR, MEK–MAPK, and PI3K–AKT/mTOR pathways. F Western blot analysis of paired parental, and MR cells. p-ERK phosphorylated ERK, t-ERK total ERK. Band density was quantified for each protein and each MR cell line was normalized to its parental cell line. Data shown in A, B, and F are representative of at least three independent experiments.

Using these models, we next investigated the cellular identified by RNA-seq translated to kinome reprogram- pathways responsible for the MCL-1 inhibitor-resistant ming in SUDHL-16 MR cells with the activation of many state. We first examined the expression of other anti- kinase pathways, including the BTK, MEK, and ERK apoptotic BCL-2 family members. Western blot analysis pathways (Fig. 1E). Increased MEK/ERK signaling was demonstrated that MR lymphoma cells exhibited sig- confirmed by western blot, illustrating increased ERK nificantly increased expression of BCL-2, but only mini- phosphorylation and BIM downregulation in S63845- mal changes in BCL-XL compared to parental cells in resistant lines (SUDHL-16, HBL-2, Mino, Marver-1, these MCL and DLBCL lines and primary sample (Figs. Fig. 1F). Collectively, these data demonstrated that tran- 1B and S1D). To determine the functional role of BCL-2 scriptome and kinome reprogramming in MR lymphoma in conferring S63845 resistance, we applied CRISPR/Cas9 cells were associated with upregulation of the MEK–ERK, editing to knockdown (KD) BCL-2 expression in resistant AKT–mTOR, and BCR pathways, which may converge on cells (SUDHL-16, Mino). These experiments revealed that BCL-2 and BIM to promote S63845 resistance. BCL-2-KD MR cells exhibited loss of cell viability (Fig. To determine the functional role of transcriptome and S1E). Importantly, BCL-2-KD reversed the resistance to kinome reprogramming in BCL-2 family protein expres- MCL-1 inhibitor in S63845-selected cell lines. Consistent sion and S63845 resistance, a drug sensitivity screen with a reduction in BCL-2 dependence, BCL-2-KD MR composed of 31 small-molecule kinase inhibitors5,7,10 was lines also demonstrated a decreased sensitivity to BCL-2 performed on paired parental and MR cells (SUDHL-16, antagonist, ABT-199 (Figs. 1C and S1F). However, the Mino, HBL-2). Additionally, we used S63845 as an decrease in ABT-199 sensitivity was not as dramatic as the “anchor” to determine the key signaling inhibitors that increase in S63845 sensitivity, which we attributed to the reinstated S63845 sensitivity in resistant cells. In line with remaining expression of BCL-2 as well as the strong our transcriptome and kinome results, MR cells exhibited potency and selectivity of ABT-199. To further confirm higher sensitivity to inhibitors of the MEK (Trametinib), the importance of BCL-2 in MCL-1 inhibitor resistance, ERK (SCH772984), and BCR pathways (Ibrutinib, R406, we tested the effect of ABT-199 in MR lines and found Fig. S2A). Importantly, the combination of S63845 with that similar to BCL-2 KD, BCL-2 inhibition enhanced the these inhibitors showed enhanced potencies against MR potency of S63845 in these cells (Fig. S1G). Together, lines (Fig. 2A). Cell viability and colony formation assays these data indicated that altered dependency on BCL-2 validated synergistic effects of the combination of S63845 contributed to S63845 resistance. with Trametinib or SCH772984 in all tested MR lines Next, we performed RNA-sequencing on parental and (Fig. S2B, C). Similar enhanced effects of these combi- resistant SUDHL-16 cells. Analysis of the transcriptomes nation treatments were observed in MCL and DLBCL cell of the sensitive and resistant cells revealed a set of dif- lines with pre-existing MCL-1 inhibitor resistance ferentially expressed genes in the resistant phenotype, (Figs. 1A and S2D), indicating that this is an effective with 359 upregulated genes and 194 downregulated genes approach to combat both de novo and acquired resistance in MR (Fig. S1H). Implementation of gene set enrichment to MCL-1 inhibition. analysis (GSEA) revealed a significant positive enrichment Next, we capitalized on a novel ex vivo microfluidic cell- of MEK–MAPK, mTOR, and BCR pathways in SUDHL- based platform5,7,10 to assess the response of a panel of 16 MR cells (Fig. 1D). Chemical activity-based proteomic kinase inhibitors as well as the combination of S63845 profiling7,10 was performed in parallel on paired with these kinase inhibitors in a 3D reconstructed tumor SUDHL-16-sensitive and -resistant cells. Consistent with microenvironment on primary MCL samples collected our previous findings5,10, the gene expression programs from lymph node and peripheral blood11,12. Again, we

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A SUDHL-16 Mino HBL-2 B 150 MCL-98 MCL-80 Sensitivity (AUC) 100 0100

Target 50 MR DMSO MR DMSO MR + MCL-1i MR DMSO MR + MCL-1i Inhibitor MR + MCL-1i BCL-2/BCL-XL ABT-263 0 BCL-2 ABT-199 150 MCL-99 MCL-83 Topo II Doxorubicin CDK12 THZ531 100

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F TNFA_Signaling_via_NFKB NES Size Oxidative_Phosphorylation 0.5 D SUDHL-16 MR S63845 - + -- 3 1.0 Trametinib --- + E2F_Targets 1.5 SCH772984 ---+ DNA_Repair 2.0 2 PI3K_AKT_MTOR_Signaling -log10(FDR qValue) BIM MTORC1_Signaling

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BCL-2 1 1.00 0.96 0.69 0.81 0 β-Actin 0 12 NES (S63845 AUC High to Low)

Fig. 2 (See legend on next page.)

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(see ﬁgure on previous page) Fig. 2 MCL-1 as a novel vulnerability for combination therapy in mantle cell lymphoma (MCL) and diffuse large B cell lymphoma (DLBCL). A Heatmap of AUCs of drug–response curves from image-based cell-viability assays performed in MR cells with and without the presence of S63845 as an anchor drug for indicated cell lines. B Left: Image-based cell-viability assays of primary MCL and DLBCL samples co-cultured with stroma cells in response to treatment with S63845, SCH772984, or S63845+SCH772984. Right: Image-based cell-viability assays of primary patient samples co- cultured with stroma cells in response to treatment with S63845, Trametinib, or S63845+Trametinib. C Quartile box plots of drug sensitivity as determined by AUCs of image-based cell-viability assays in primary MCL samples. P values between treatment groups were calculated with the Friedman Conover Test. Top: Primary samples treated with S63845, SCH772984, or S63845+SCH772984. n = 7. Bottom: Primary samples treated with S63845, Trametinib, or S63845+Trametinib. n = 13. D Western blot analysis of BCL-2 family proteins in MR cells after 48 h treatment with S63845 (2 μM), Trametinib (2 μM), or SCH772984 (2 μM). E Heatmap of top differentially expressed genes between primary S63845-resistant and S63845- sensitive patient samples deﬁned by AUCs calculated from image-based cell-viability assays. F Scatterplot of GSEA-positive NES of the Hallmarks gene set from MsigDB in primary patient samples phenotypically characterized by S63845 sensitivity as determined by AUCs calculated from image-based cell-viability assays. FDRq cut-off of 0.25. Data shown in A and D are representative of at least three independent experiments.

observed enhanced effects of S63845 combined with 2 (refs. 13,14) and post-translational downregulation of Trametinib or SCH772984 and synergistic effects of both BIM15. To this end, combinatorial therapies of MCL-1 combinations in S63845-resistant primary MCL samples inhibitor with MEK, ERK, or BCR inhibitors (to decrease (Fig. 2B, C). Mechanistically, western blot analysis showed BCL-2 and increase BIM) exhibited potent synergistic that both MEK and ERK inhibition induced BCL-2 effects against MCL-1 inhibitor-resistant lymphoma downregulation and BIM upregulation in MR lines ex vivo and in vivo. Together, these studies provide a (SUDHL-16). Furthermore, the combination of S63845 rationale for MCL-1 inhibition in MCL/DLBCL and with Trametinib or SCH772984 triggered increased PARP present MCL-1 inhibition-based combination strategies cleavage compared to S63845, MEK, or ERK inhibitor to MCL-1-dependent and MCL-1 inhibitor-resistant B alone in SUDHL-16 and Mino-resistant models (Figs. 2D cell lymphomas. and S2E). These data indicate that kinome reprograming linked to the MEK and ERK pathways contributed to Acknowledgements MCL-1 inhibitor resistance via regulation of the BCL-2 This work was supported in part by grants from the National Cancer Institute fi CA179062, CA233601, and CA241713 (to J.T), a grant from the Lymphoma family pro le (BCL-2, BIM), and represent a novel vul- Research Foundation and a grant from Florida State Live Like Bella Pediatric nerability in MCL-1 inhibitor-resistant lymphoma. Cancer Research Initiative (to J.T.). Finally, we integrated RNA-seq data with drug response profiling data for 24 primary MCL samples. We deter- Author details 1 fi mined drug sensitivity by calculating the area under curve Chemical Biology and Molecular Medicine Program, H. Lee Mof tt Cancer Center & Research Institute, Tampa, FL 33612, USA. 2Department of Malignant (AUC) and the half maximal effective concentration Hematology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 3 fi (EC50) of each drug for every patient. As shown in Fig. 2E, 33612, USA. Department of Tumor Biology, H. Lee Mof tt Cancer Center & 4 using the AUC of S63845, we segregated these primary Research Institute, Tampa, FL 33612, USA. Department of Computer Science, University of Central Florida, Orlando, FL 32816, USA. 5Department of samples into responders (n = 10) and non-responders Hematopathology and Laboratory Medicine, H. Lee Moffitt Cancer Center & (n = 14) and correlated S63845 response with the gene Research Institute, Tampa, FL 33612, USA expression profile of each sample. Consistent with our Author contributions in vitro results, the investigation of differentially expressed Conception and design: J.T., X.Z., and M.Y.W. Performed experiments, collected, genes of these two response groups by GSEA revealed and assembled the data: M.Y.W., T.L., X.Z., T.L., J.G., Y.R., B.D.S., K.H.S., W.Z., and enrichment of mTOR, MEK–ERK, and BCR pathway- J.T. regulated genes in S63845-resistant primary samples Conflict of interest (Figs. 2F and S2F). Collectively, these data identify a tar- The authors declare that they have no conflict of interest. getable MEK–ERK dependent regulation of MCL-1 inhibitor resistance with significant translational potential in Publisher’s note future clinical combinations trials. Springer Nature remains neutral with regard to jurisdictional claims in fi In conclusion, we identified MCL-1 as a key determi- published maps and institutional af liations. nant of cell survival and growth in MCL and DLBCL Supplementary Information accompanies this paper at (https://doi.org/ lymphomas, which conferred exquisite sensitivity to 10.1038/s41408-020-00402-2). MCL-1 inhibition. Using pharmacogenomics and chemical proteomics, we identified that MEK–ERK and BCR Received: 19 August 2020 Revised: 11 December 2020 Accepted: 16 December 2020 pathway activation drive MCL-1 inhibitor resistance in these lymphomas via transcriptional upregulation of BCL-

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