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Several therapeutic agents have been approved for treating multiple myeloma (MM), a cancer of bone marrow resident plasma cells. Predictive biomarkers for drug response could help guide clinical strategies to optimize outcomes. Here, we present an integrated functional genomic analysis of tumor samples from MM patients that were assessed for their ex vivo drug sensitivity to 37 drugs, clinical variables, cytogenetics, mutational profiles, and transcriptomes. This analysis revealed a MM transcriptomic topology that generates "footprints" in association with ex vivo drug sensitivity that have both predictive and mechanistic applications. Validation of the transcriptomic footprints for the anti-CD38 monoclonal antibody daratumumab and the nuclear export inhibitor selinexor demonstrated that these footprints can accurately classify clinical responses. The analysis further revealed that daratumumab and selinexor have anti-correlated mechanisms of resistance, and treatment with a selinexor-based regimen immediately after a daratumumab-containing regimen was associated with improved survival in three independent clinical trials, supporting an evolutionary-based strategy involving sequential therapy. These findings suggest that this unique repository and computational framework can be leveraged to inform underlying biology and to identify therapeutic strategies to improve treatment of MM.

The nuclear export receptor Exportin 1 (XPO1/CRM1) is often overexpressed in cancer cells resulting in aberrant localization of many cancer-related protein cargoes. The XPO1 inhibitor and cancer drug selinexor (KPT-330), and its analog KPT-185, block XPO1-cargo binding thereby restoring cargo localization. Selinexor binding induces cullin-RING E3 ubiquitin ligase (CRL) substrate receptor ASB8-mediated XPO1 degradation. Here we reveal the mechanism of inhibitor-XPO1 engagement by CRL5ASB8. Cryogenic electron microscopy (cryo-EM) structures show ASB8 binding to a large surface of selinexor/KPT-185-XPO1 that includes a three-dimensional degron unique to the drug-bound exportin. The structure explains weak XPO1-ASB8 binding in the absence of selinexor/KPT-185 that is unproductive for proteasomal degradation, and the substantial affinity increase upon selinexor/KPT-185 conjugation, which results in CRL5 ASB8 -mediated XPO1 ubiquitination. In contrast to previously characterized small molecule degraders, which all act as molecular glues, selinexor/KPT-185 binds extensively to XPO1 but hardly contacts ASB8. Instead, selinexor/KPT-185 binds XPO1 and stabilizes a unique conformation of the NES/inhibitor-binding groove that binds ASB8. Selinexor/KPT-185 is an allosteric degrader. We have explained how drug-induced protein degradation is mediated by a CRL5 system through an allosteric rather than a molecular glue mechanism, expanding the modes of targeted protein degradation beyond the well-known molecular glues of CRL4.

Myeloid-derived suppressor cells (MDSCs) are a main driver of immunosuppression in tumors. Understanding the mechanisms that determine the development and immunosuppressive function of these cells could provide new therapeutic targets to improve antitumor immunity. Here, using preclinical murine models, we discovered that exportin 1 (XPO1) expression is upregulated in tumor MDSCs and that this upregulation is induced by IL-6-induced STAT3 activation during MDSC differentiation. XPO1 blockade transforms MDSCs into T-cell-activating neutrophil-like cells, enhancing the antitumor immune response and restraining tumor growth. Mechanistically, XPO1 inhibition leads to the nuclear entrapment of ERK1/2, resulting in the prevention of ERK1/2 phosphorylation following the IL-6-mediated activation of the MAPK signaling pathway. Similarly, XPO1 blockade in human MDSCs induces the formation of neutrophil-like cells with immunostimulatory functions. Therefore, our findings revealed a critical role for XPO1 in MDSC differentiation and suppressive functions; exploiting these new discoveries revealed new targets for reprogramming immunosuppressive MDSCs to improve cancer therapeutic responses., (© 2024. The Author(s), under exclusive licence to CSI and USTC.)

Alveolar soft part sarcoma (ASPS) is a rare mesenchymal malignancy driven by the ASPSCR1::TFE3 fusion. A better understanding of the mechanisms by which this oncogenic transcriptional regulator drives cancer growth is needed to help identify potential therapeutic targets. In this study, we characterized the transcriptional and chromatin landscapes of ASPS tumors and preclinical models, identifying the essential role of ASPSCR1::TFE3 in tumor cell viability by regulating core transcriptional programs involved in cell proliferation, angiogenesis, and mitochondrial biology. ASPSCR1::TFE3 directly interacted with key epigenetic regulators at enhancers and promoters to support ASPS-associated transcription. Among the effector programs driven by ASPSCR1::TFE3, cell proliferation was driven by high levels of cyclin D1 expression. Disruption of cyclin D1/CDK4 signaling led to a loss of ASPS proliferative capacity, and combined inhibition of CDK4/6 and angiogenesis halted tumor growth in xenografts. These results define the ASPS oncogenic program, reveal mechanisms by which ASPSCR1::TFE3 controls tumor biology, and identify a strategy for therapeutically targeting tumor cell-intrinsic vulnerabilities. Significance: The ASPSCR1::TFE3 fusion propels the growth of alveolar soft part sarcoma  by activating transcriptional programs that regulate proliferation, angiogenesis, mitochondrial biogenesis, and differentiation and can be therapeutically targeted to improve treatment., (©2024 American Association for Cancer Research.)