Predicting ROR1/BCL2 combination targeted therapy of small cell carcinoma of the lung
Open Access
- 4 June 2021
- journal article
- research article
- Published by Springer Science and Business Media LLC in Cell Death & Disease
- Vol. 12 (6), 1-9
- https://doi.org/10.1038/s41419-021-03855-w
Abstract
Small cell lung cancer (SCLC) remains a deadly form of cancer, with a 5-year survival rate of less than 10 percent, necessitating novel therapies. Receptor tyrosine kinase-like orphan receptor 1 (ROR1) is an oncofetal protein that is emerging as a therapeutic target and is co-expressed with BCL2 in multiple tumor types due to microRNA coregulation. We hypothesize that ROR1-targeted therapy is effective in small cell lung cancer and synergizes with therapeutic BCL2 inhibition. Tissue microarrays (TMAs) and formalin-fixed paraffin-embedded (FFPE) SCLC patient samples were utilized to determine the prevalence of ROR1 and BCL2 expression in SCLC. Eight SCLC-derived cell lines were used to determine the antitumor activity of a small molecule ROR1 inhibitor (KAN0441571C) alone and in combination with the BCL2 inhibitor venetoclax. The Chou-Talalay method was utilized to determine synergy with the drug combination. ROR1 and BCL2 protein expression was identified in 93% (52/56) and 86% (48/56) of SCLC patient samples, respectively. Similarly, ROR1 and BCL2 were shown by qRT-PCR to have elevated expression in 79% (22/28) and 100% (28/28) of SCLC patient samples, respectively. KAN0441571C displayed efficacy in 8 SCLC cell lines, with an IC50 of 500 nM or less. Synergy as defined by a combination index of <1 via the Chou-Talalay method between KAN0441571C and venetoclax was demonstrated in 8 SCLC cell lines. We have shown that ROR1 inhibition is synergistic with BCL2 inhibition in SCLC models and shows promise as a novel therapeutic target in SCLC.Keywords
Funding Information
- U.S. Department of Health & Human Services | National Institutes of Health (R35CA197706)
- Schnipke Family Endowment Fund to Support Clinical Trials and Cancer Research; the Robert and Martina Poe Small Cell Carcinoma Fund
This publication has 37 references indexed in Scilit:
- First-Line Atezolizumab plus Chemotherapy in Extensive-Stage Small-Cell Lung CancerThe New England Journal of Medicine, 2018
- First-in-class oral small molecule inhibitor of the tyrosine kinase ROR1 (KAN0439834) induced significant apoptosis of chronic lymphocytic leukemia cellsLeukemia, 2018
- New insights into stage and prognosis in small cell lung cancer: an analysis of 968 casesJournal of Thoracic Disease, 2017
- MicroRNA dysregulation to identify therapeutic target combinations for chronic lymphocytic leukemiaProceedings of the National Academy of Sciences of the United States of America, 2017
- Analysis of ROR1 Protein Expression in Human Cancer and Normal TissuesClinical Cancer Research, 2017
- ROR1 is a novel prognostic biomarker in patients with lung adenocarcinomaScientific Reports, 2016
- ROR1 sustains caveolae and survival signalling as a scaffold of cavin-1 and caveolin-1Nature Communications, 2016
- Ovarian cancer stem cells express ROR1, which can be targeted for anti–cancer-stem-cell therapyProceedings of the National Academy of Sciences of the United States of America, 2014
- ROR1, an embryonic protein with an emerging role in cancer biologyProtein & Cell, 2014
- NKX2-1/TITF1/TTF-1-Induced ROR1 Is Required to Sustain EGFR Survival Signaling in Lung AdenocarcinomaCancer Cell, 2012