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

doi:10.1016/j.isci.2023.107302

Targeting ITGB4/SOX2-driven lung cancer stem cells using proteasome inhibitors

iScience. 2023 Jul 10;26(8):107302. doi: 10.1016/j.isci.2023.107302. eCollection 2023 Aug 18.

Authors

Linlin Guo^{1

2}, Atish Mohanty¹, Sharad Singhal¹, Saumya Srivastava¹, Arin Nam¹, Charles Warden³, Sravani Ramisetty¹, Yate-Ching Yuan⁴, Hyejin Cho³, Xiwei Wu³, Aimin Li⁵, Manik Vohra⁶, Srinivas Vinod Saladi^{6

7}, Deric Wheeler⁸, Leonidas Arvanitis⁵, Erminia Massarelli¹, Prakash Kulkarni^{1

9}, Yiming Zeng², Ravi Salgia¹

Affiliations

¹ Department of Medical Oncology and Experimental Therapeutics, City of Hope National Medical Center, Duarte, CA 91010, USA.
² Department of Pulmonary and Critical Care Medicine, The Second Affiliated Hospital of Fujian Medical University, Respirology Medicine Centre of Fujian Province, Quanzhou, China.
³ Integrative Genomics Core, Beckman Research Institute, City of Hope, Monrovia, CA 91016, USA.
⁴ Divison of Translational Bioinformatics, Beckman Research Institute, City of Hope, Duarte, CA 91010, USA.
⁵ Department of Pathology, City of Hope National Medical Center, Duarte, CA 91010, USA.
⁶ Department of Otolaryngology Head and Neck Surgery, Harvard Medical School, Boston, MA, USA.
⁷ Broad Institute of MIT and Harvard, Cambridge, MA, USA.
⁸ Department of Human Oncology, University of Wisconsin, Madison, WI, USA.
⁹ Department of Systems Biology, City of Hope National Medical Center, Duarte, CA 91010, USA.

Abstract

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.

Keywords: Cancer; Cell biology; Molecular biology; Transcriptomics.