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

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.

• Authors: Walter Z Wang, Konstantin Shilo, Joseph M Amann, Alyssa Shulman, Mohammad Hojjat-Farsangi, Håkan Mellstedt, Johan Schultz, Carlo M Croce, David P Carbone
• Journal: Cell death & disease (Cell Death Dis) Vol. 12 Issue 6 Pg. 577 (06 04 2021) ISSN: 2041-4889 [Electronic] England
• PMID: 34088900 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• BCL2 protein, human
• Bridged Bicyclo Compounds, Heterocyclic
• Protein Kinase Inhibitors
• Proto-Oncogene Proteins c-bcl-2
• Sulfonamides
• ROR1 protein, human
• Receptor Tyrosine Kinase-like Orphan Receptors
• venetoclax

Topics

• Antineoplastic Combined Chemotherapy Protocols (pharmacology)
• Bridged Bicyclo Compounds, Heterocyclic (administration & dosage, pharmacology)
• Cell Line, Tumor
• Drug Synergism
• Humans
• Lung Neoplasms (drug therapy, genetics, metabolism)
• Molecular Targeted Therapy
• Protein Kinase Inhibitors (administration & dosage, pharmacology)
• Proto-Oncogene Proteins c-bcl-2 (antagonists & inhibitors, biosynthesis, genetics)
• Receptor Tyrosine Kinase-like Orphan Receptors (antagonists & inhibitors, biosynthesis, genetics)
• Small Cell Lung Carcinoma (drug therapy, genetics, metabolism)
• Sulfonamides (administration & dosage, pharmacology)
• Survival Analysis