Teriflunomide/leflunomide synergize with chemotherapeutics by decreasing mitochondrial fragmentation via DRP1 in SCLC
Tamara Mirzapoiazova,
Liz Tseng,
Bolot Mambetsariev,
Haiqing Li,
Chih-Hong Lou,
Alex Pozhitkov,
Sravani Keerthi Ramisetty,
Sangkil Nam,
Isa Mambetsariev,
Brian Armstrong,
Jyoti Malhotra,
Leonidas Arvanitis,
Mohd Wasim Nasser,
Surinder K. Batra,
Steven T. Rosen,
Deric L. Wheeler,
Sharad S. Singhal,
Prakash Kulkarni,
Ravi Salgia
Affiliations
Tamara Mirzapoiazova
Department of Medical Oncology and Therapeutics Research, City of Hope National Medical Center, Duarte, CA 91010, USA
Liz Tseng
Department of Shared Resources, Light Microscopy Digital Imaging Core, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA 91010, USA
Bolot Mambetsariev
Department of Medical Oncology and Therapeutics Research, City of Hope National Medical Center, Duarte, CA 91010, USA
Haiqing Li
Integrative Genomics Core, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA 91010, USA
Chih-Hong Lou
Genome Editing Core, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA 91010, USA
Alex Pozhitkov
Division of Research Informatics, Beckman Research Institute, City of Hope, Duarte, CA 91010, USA
Sravani Keerthi Ramisetty
Department of Medical Oncology and Therapeutics Research, City of Hope National Medical Center, Duarte, CA 91010, USA
Sangkil Nam
Department of Shared Resources, Molecular Pathology Core, City of Hope National Medical Center, Duarte, CA 91010, USA
Isa Mambetsariev
Department of Medical Oncology and Therapeutics Research, City of Hope National Medical Center, Duarte, CA 91010, USA
Brian Armstrong
Department of Shared Resources, Light Microscopy Digital Imaging Core, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA 91010, USA
Jyoti Malhotra
Department of Medical Oncology and Therapeutics Research, City of Hope National Medical Center, Duarte, CA 91010, USA
Leonidas Arvanitis
Department of Pathology, City of Hope, Duarte, CA 91010, USA
Mohd Wasim Nasser
Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198, USA
Surinder K. Batra
Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198, USA
Steven T. Rosen
Hematology Malignancies and Stem Cell Transplantation Institute, Gehr Family Center for Leukemia Research, City of Hope National Medical Center, Duarte, CA 91010, USA
Deric L. Wheeler
Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Wisconsin Institute for Medical Research, Madison, WI, USA
Sharad S. Singhal
Department of Medical Oncology and Therapeutics Research, City of Hope National Medical Center, Duarte, CA 91010, USA
Prakash Kulkarni
Department of Medical Oncology and Therapeutics Research, City of Hope National Medical Center, Duarte, CA 91010, USA; Department of Systems Biology, City of Hope National Medical Center, Duarte, CA 91010, USA
Ravi Salgia
Department of Medical Oncology and Therapeutics Research, City of Hope National Medical Center, Duarte, CA 91010, USA; Corresponding author
Summary: Although up to 80% small cell lung cancer (SCLC) patients’ response is good for first-line chemotherapy regimen, most patients develop recurrence of the disease within weeks to months. Here, we report cytostatic effect of leflunomide (Leflu) and teriflunomide (Teri) on SCLC cell proliferation through inhibition of DRP1 phosphorylation at Ser616 and decreased mitochondrial fragmentation. When administered together, Teri and carboplatin (Carbo) act synergistically to significantly inhibit cell proliferation and DRP1 phosphorylation, reduce abundance of intermediates in pyrimidine de novo pathway, and increase apoptosis and DNA damage. Combination of Leflu&Carbo has anti-tumorigenic effect in vivo. Additionally, lurbinectedin (Lur) and Teri potently and synergistically inhibited spheroid growth and depleted uridine and DRP1 phosphorylation in mouse tumors. Our results suggest combinations of Carbo and Lur with Teri or Leflu are efficacious and underscore how the relationship between DRP1/DHODH and mitochondrial plasticity serves as a potential therapeutic target to validate these treatment strategies in SCLC clinical trials.
