Targeting ITGB4/SOX2-driven lung cancer stem cells using proteasome inhibitors
Linlin Guo,
Atish Mohanty,
Sharad Singhal,
Saumya Srivastava,
Arin Nam,
Charles Warden,
Sravani Ramisetty,
Yate-Ching Yuan,
Hyejin Cho,
Xiwei Wu,
Aimin Li,
Manik Vohra,
Srinivas Vinod Saladi,
Deric Wheeler,
Leonidas Arvanitis,
Erminia Massarelli,
Prakash Kulkarni,
Yiming Zeng,
Ravi Salgia
Affiliations
Linlin Guo
Department of Medical Oncology and Experimental Therapeutics, City of Hope National Medical Center, Duarte, CA 91010, USA; Department of Pulmonary and Critical Care Medicine, The Second Affiliated Hospital of Fujian Medical University, Respirology Medicine Centre of Fujian Province, Quanzhou, China
Atish Mohanty
Department of Medical Oncology and Experimental Therapeutics, City of Hope National Medical Center, Duarte, CA 91010, USA
Sharad Singhal
Department of Medical Oncology and Experimental Therapeutics, City of Hope National Medical Center, Duarte, CA 91010, USA
Saumya Srivastava
Department of Medical Oncology and Experimental Therapeutics, City of Hope National Medical Center, Duarte, CA 91010, USA
Arin Nam
Department of Medical Oncology and Experimental Therapeutics, City of Hope National Medical Center, Duarte, CA 91010, USA
Charles Warden
Integrative Genomics Core, Beckman Research Institute, City of Hope, Monrovia, CA 91016, USA
Sravani Ramisetty
Department of Medical Oncology and Experimental Therapeutics, City of Hope National Medical Center, Duarte, CA 91010, USA
Yate-Ching Yuan
Divison of Translational Bioinformatics, Beckman Research Institute, City of Hope, Duarte, CA 91010, USA
Hyejin Cho
Integrative Genomics Core, Beckman Research Institute, City of Hope, Monrovia, CA 91016, USA
Xiwei Wu
Integrative Genomics Core, Beckman Research Institute, City of Hope, Monrovia, CA 91016, USA
Aimin Li
Department of Pathology, City of Hope National Medical Center, Duarte, CA 91010, USA
Manik Vohra
Department of Otolaryngology Head and Neck Surgery, Harvard Medical School, Boston, MA, USA
Srinivas Vinod Saladi
Department of Otolaryngology Head and Neck Surgery, Harvard Medical School, Boston, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA
Deric Wheeler
Department of Human Oncology, University of Wisconsin, Madison, WI, USA
Leonidas Arvanitis
Department of Pathology, City of Hope National Medical Center, Duarte, CA 91010, USA
Erminia Massarelli
Department of Medical Oncology and Experimental Therapeutics, City of Hope National Medical Center, Duarte, CA 91010, USA
Prakash Kulkarni
Department of Medical Oncology and Experimental Therapeutics, City of Hope National Medical Center, Duarte, CA 91010, USA; Department of Systems Biology, City of Hope National Medical Center, Duarte, CA 91010, USA
Yiming Zeng
Department of Pulmonary and Critical Care Medicine, The Second Affiliated Hospital of Fujian Medical University, Respirology Medicine Centre of Fujian Province, Quanzhou, China; Corresponding author
Ravi Salgia
Department of Medical Oncology and Experimental Therapeutics, City of Hope National Medical Center, Duarte, CA 91010, USA; Corresponding author
Summary: This study investigates the role of integrin β4 (ITGB4) and stemness-associated factor SOX2 in platinum resistance in lung squamous cell carcinoma (LUSC). The expression of SOX2 and ITGB4 is found to be high in all LUSC subtypes, but the impact of ITGB4 expression on overall patient survival varies by subtype. Cancer stem cells (CSCs) isolated from LUSC patients were found to be resistant to cisplatin, but knocking down ITGB4 or SOX2 sensitized them to cisplatin. Carfilzomib (CFZ) synergized with cisplatin and suppressed CSC growth by inhibiting ITGB4 and SOX2 expression. Additionally, CFZ was found to inhibit SOX2 expression epigenetically by inhibiting histone acetylation at the SOX2 promoter site. CFZ also suppressed the growth of SOX2-dependent small cell lung cancer cells in vitro and in vivo. The study highlights the unique function of CFZ as a transcriptional suppressor of SOX2, independent of its proteasome inhibitory function.
