Abstract
Exportin-1 (XPO1), the main soluble nuclear export receptor in eukaryotic cells, is frequently overexpressed in diffuse large B-cell lymphoma (DLBCL). A selective XPO1 inhibitor, selinexor, received approval as single agent for relapsed or refractory (R/R) DLBCL. Elucidating the mechanisms by which XPO1 overexpression supports cancer cells could facilitate further clinical development of XPO1 inhibitors. We uncovered here that XPO1 overexpression increases tolerance to genotoxic stress, leading to a poor response to chemoimmunotherapy. Upon DNA damage induced by MYC expression or exogenous compounds, XPO1 bound and exported EIF4E and THOC4 carrying DNA damage repair mRNAs, thereby increasing synthesis of DNA damage repair proteins under conditions of increased turnover. Consequently, XPO1 inhibition decreased the capacity of lymphoma cells to repair DNA damage and ultimately resulted in increased cytotoxicity. In a phase I clinical trial conducted in R/R DLBCL, the combination of selinexor with second-line chemoimmunotherapy was tolerated with early indication of efficacy. Overall, this study reveals that XPO1 overexpression plays a critical role in the increased tolerance of cancer cells to DNA damage while providing new insights to optimize the clinical development of XPO1 inhibitors.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 101-117 |
| Number of pages | 17 |
| Journal | Cancer Research |
| Volume | 184 |
| Issue number | 1 |
| DOIs | |
| State | Published - Jan 1 2024 |
Funding
S.C. Rutherford reports grants from Karyopharm during the conduct of the study; personal fees from ADC, BMS, Genmab, Karyopharm, Kite; other support from Constellation, Genentech; and personal fees from Seagen outside the submitted work. N. Kotlov reports other support from Bostongene Corp. during the conduct of the study and other support from Bostongene Corp. outside the submitted work; in addition, N. Kotlov has a patent for Tumor Microenvironment-Based Methods for Assessing CAR-T and Other Immunotherapies issued to Bostongene Corp. J. Lara-Garcia reports ownership of stock in Johnson & Johnson and Pfizer. J.N. Allan reports personal fees from AbbVie, Adaptive Therapeutics, ADC Therapeutics, AstraZeneca; grants and personal fees from BeiGene, Gen-entech, Janssen; personal fees from Epizyme, Lava Therapeutics, Lilly, Pharma-cyclics; and grants and personal fees from TG Therapeutics outside the submitted work. J. Ruan reports grants and personal fees from AstraZeneca; grants from BMS, Genentech, Daiichi Sankyo; personal fees from Janssen, SecuraBio; and personal fees from Kite Pharma outside the submitted work. S.A. Mayer reports grants from Karyopharm during the conduct of the study. J.P. Leonard reports personal fees from AbbVie, Astellas, AstraZeneca, Bayer, Beigene, BMS, Calithera, Constellation, Caribou Biosciences, Eisai, Lilly, Epizyme, Genmab, Grail, Incyte, Janssen, MEI Pharma, Merck, Mustang Bio, Novartis, Pfizer, Seagen, Second Genome; grants and personal fees from Roche/Genentech; and personal fees from Sutro outside the submitted work. P. Martin reports other support from Kar-yopharm during the conduct of the study and personal fees from AstraZeneca, Beigene, Genentech, Janssen, Merck, and BMS outside the submitted work. L. Cerchietti reports grants from NIH, NCI, Leukemia and Lymphoma Society and Karyopharm, Inc. during the conduct of the study and grants from Celgene outside the submitted work. No disclosures were reported by the other authors. ShaoNing Yang provided technical assistance. Dr. Kristy Richards (deceased) provided patient care. Silvia Senese, Trisha Ali-Shaw, Riyaad Rahim, Amelyn Rodriguez, Arcania Garcia, and Jennifer Santamala provided clinical trial coordination and patient care. R. Marullo was supported by NIH training grant T32 CA203702. Funding for this work was provided by the Leukemia and Lymphoma Society (LLS TRP R6510–19), the NIH-NCI (R01CA242069 and R01CA249843), and a research grant from Karyopharm, Inc.
ASJC Scopus subject areas
- Oncology
- Cancer Research
