Pan-ERBB kinase inhibition augments CDK4/6 inhibitor efficacy in oesophageal squamous cell carcinoma. Issue 4 (31st March 2021)

• Record Type: Journal Article
• Authors: Zhou, Jin; Wu, Zhong; Zhang, Zhouwei; Goss, Louisa; McFarland, James; Nagaraja, Ankur; Xie, Yingtian; Gu, Shengqing; Peng, Ke; Zeng, Yong; Zhang, Xiaoyang; Long, Henry; Nakagawa, Hiroshi; Rustgi, Anil; Diehl, J Alan; Meyerson, Matthew; Wong, Kwok-Kin; Bass, Adam
• Is Part Of: Gut. Volume 71:Issue 4(2022)
• Page Start: 665
• Page End: 675
• Publication Date: 2021-03-31
• Subjects: oesophageal cancer -- cell cycle control -- pharmacogenomics -- pharmacotherapy; Gastroenterology -- Periodicals; 616.33
• DOI: 10.1136/gutjnl-2020-323276
• Languages: English
• ISSNs: 0017-5749

Abstract

Abstract : Objective: Oesophageal squamous cell carcinoma (OSCC), like other squamous carcinomas, harbour highly recurrent cell cycle pathway alterations, especially hyperactivation of the CCND1/CDK4/6 axis, raising the potential for use of existing CDK4/6 inhibitors in these cancers. Although CDK4/6 inhibition has shown striking success when combined with endocrine therapy in oestrogen receptor positive breast cancer, CDK4/6 inhibitor palbociclib monotherapy has not revealed evidence of efficacy to date in OSCC clinical studies. Herein, we sought to elucidate the identification of key dependencies in OSCC as a foundation for the selection of targets whose blockade could be combined with CDK4/6 inhibition. Design: We combined large-scale genomic dependency and pharmaceutical screening datasets with preclinical cell line models, to identified potential combination therapies in squamous cell cancer. Results: We identified sensitivity to inhibitors to the ERBB family of receptor kinases, results clearly extending beyond the previously described minority of tumours with EGFR amplification/dependence, specifically finding a subset of OSCCs with dual dependence on ERBB3 and ERBB2. Subsequently. we demonstrated marked efficacy of combined pan-ERBB and CDK4/6 inhibition in vitro and in vivo. Furthermore, we demonstrated that squamous lineage transcription factor KLF5 facilitated activation of ERBBs in OSCC. Conclusion: These results provide clear rationale for development of combined ERBB and CDK4/6 inhibition in these cancers and raises the potential for KLF5 expression as a candidate biomarker to guide the use of these agents. These data suggested that by combining existing Food and Drug Administration (FDA)-approved agents, we have the capacity to improve therapy for OSCC and other squamous cancer.