Predicting ROR1/BCL2 combination targeted therapy of small cell carcinoma of the lung
| Autor: | Walter Wang, Johan Schultz, David P. Carbone, Mohammad Hojjat-Farsangi, Håkan Mellstedt, Joseph M. Amann, Alyssa Shulman, Konstantin Shilo, Carlo M. Croce |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Cancer Research
Lung Neoplasms medicine.medical_treatment Immunology Receptor Tyrosine Kinase-like Orphan Receptors Small-cell carcinoma Article Small-cell lung cancer Targeted therapy Cellular and Molecular Neuroscience chemistry.chemical_compound Targeted therapies Cell Line Tumor microRNA Antineoplastic Combined Chemotherapy Protocols medicine Humans Molecular Targeted Therapy Receptor Cancer genetics Protein Kinase Inhibitors neoplasms Sulfonamides Tissue microarray QH573-671 business.industry Venetoclax Cancer Drug Synergism Cell Biology medicine.disease Bridged Bicyclo Compounds Heterocyclic Small Cell Lung Carcinoma Survival Analysis respiratory tract diseases chemistry Proto-Oncogene Proteins c-bcl-2 ROR1 Cancer research business Cytology |
| Zdroj: | Cell Death and Disease, Vol 12, Iss 6, Pp 1-9 (2021) Cell Death & Disease |
| ISSN: | 2041-4889 |
| Popis: | 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 |
| Databáze: | OpenAIRE |
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