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Predicting ROR1/BCL2 combination targeted therapy of small cell carcinoma of the lung

Authors :
Walter Z. Wang
Konstantin Shilo
Joseph M. Amann
Alyssa Shulman
Mohammad Hojjat-Farsangi
Håkan Mellstedt
Johan Schultz
Carlo M. Croce
David P. Carbone
Source :
Cell Death and Disease, Vol 12, Iss 6, Pp 1-9 (2021)
Publication Year :
2021
Publisher :
Nature Publishing Group, 2021.

Abstract

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

Subjects

Subjects :
Cytology
QH573-671

Details

Language :
English
ISSN :
20414889
Volume :
12
Issue :
6
Database :
Directory of Open Access Journals
Journal :
Cell Death and Disease
Publication Type :
Academic Journal
Accession number :
edsdoj.8e3d803832bd442687414f1eec0b50ef
Document Type :
article
Full Text :
https://doi.org/10.1038/s41419-021-03855-w