Targeting EZH2 to overcome the resistance to immunotherapy in lung cancer

Daniel Sanghoon Shin; Kevin Park; Edward Garon; Steven Dubinett

doi:10.1053/j.seminoncol.2022.06.005

Targeting EZH2 to overcome the resistance to immunotherapy in lung cancer

Semin Oncol. 2022 Jul 2:S0093-7754(22)00045-8. doi: 10.1053/j.seminoncol.2022.06.005. Online ahead of print.

Authors

Daniel Sanghoon Shin¹, Kevin Park², Edward Garon³, Steven Dubinett⁴

Affiliations

¹ Department of Medicine, Division of Hematology/Oncology, University of California Los Angeles, Los Angeles, CA, USA; VA Greater Los Angeles Healthcare System, Division of Hematology/Oncology, CA, USA; Member of Molecular Biology Institute, UCLA, CA, USA; Member of Jonsson Comprehensive Cancer Center, UCLA, CA, USA. Electronic address: dsshin@mednet.ucla.edu.
² Department of Medicine, Division of Hematology/Oncology, University of California Los Angeles, Los Angeles, CA, USA.
³ Department of Medicine, Division of Hematology/Oncology, University of California Los Angeles, Los Angeles, CA, USA; Member of Jonsson Comprehensive Cancer Center, UCLA, CA, USA.
⁴ Department of Medicine, Division of Pulmonary and Critical Care Medicine, University of California Los Angeles, Los Angeles, CA, USA; Departments of Pathology, Laboratory Medicine, University of California Los Angeles, Los Angeles, CA, USA; Department of Molecular and Medical Pharmacology University of California Los Angeles, CA, USA; VA Greater Los Angeles Healthcare System, Division of Hematology/Oncology, CA, USA; Member of Molecular Biology Institute, UCLA, CA, USA; Member of Jonsson Comprehensive Cancer Center, UCLA, CA, USA.

PMID: 35851153
DOI: 10.1053/j.seminoncol.2022.06.005

Abstract

Unleashing the immune system to fight cancer has been a major breakthrough in cancer therapeutics since 2014 when anti-PD-1 antibodies (pembrolizumab and nivolumab) were approved for patients with metastatic melanoma. Therapeutic indications have rapidly expanded for many types of advanced cancer, including lung cancer. A variety of antibodies targeting the PD-1/PD-L1 checkpoint are contributing to this paradigm shift. The field now confronts two salient challenges: first, to improve the therapeutic outcome given the low response rate across the histologies; second, to identify biomarkers for improved patient selection. Pre-clinical and clinical studies are underway to evaluate combinatorial treatments to improve the therapeutic outcome paired with correlative studies to identify the factors associated with response and resistance. One of the emerging strategies is to combine epigenetic modifiers with immune checkpoint blockade (ICB) based on the evidence that targeting epigenetic elements can enhance anti-tumor immunity by reshaping the tumor microenvironment (TME). We will briefly review pleotropic biological functions of enhancer of zeste homolog 2 (EZH2), the enzymatic subunit of polycomb repressive complex 2 (PRC2), clinical developments of oral EZH2 inhibitors, and potentially promising approaches to combine EZH2 inhibitors and PD-1 blockade for patients with advanced solid tumors, focusing on lung cancer.

Keywords: EZH2; Immunotherapy; Lung cancer; PD-1 blockade; PRC2.