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Ref Type Journal Article
PMID (20576088)
Authors Bauer JA, Ye F, Marshall CB, Lehmann BD, Pendleton CS, Shyr Y, Arteaga CL, Pietenpol JA
Title RNA interference (RNAi) screening approach identifies agents that enhance paclitaxel activity in breast cancer cells.
Journal Breast cancer research : BCR
Vol 12
Issue 3
Date 2010
URL
Abstract Text Paclitaxel is a widely used drug in the treatment of patients with locally advanced and metastatic breast cancer. However, only a small portion of patients have a complete response to paclitaxel-based chemotherapy, and many patients are resistant. Strategies that increase sensitivity and limit resistance to paclitaxel would be of clinical use, especially for patients with triple-negative breast cancer (TNBC).We generated a gene set from overlay of the druggable genome and a collection of genomically deregulated gene transcripts in breast cancer. We used loss-of-function RNA interference (RNAi) to identify gene products in this set that, when targeted, increase paclitaxel sensitivity. Pharmacological agents that targeted the top scoring hits/genes from our RNAi screens were used in combination with paclitaxel, and the effects on the growth of various breast cancer cell lines were determined.RNAi screens performed herein were validated by identification of genes in pathways that, when previously targeted, enhanced paclitaxel sensitivity in the pre-clinical and clinical settings. When chemical inhibitors, CCT007093 and mithramycin, against two top hits in our screen, PPMID and SP1, respectively, were used in combination with paclitaxel, we observed synergistic growth inhibition in both 2D and 3D breast cancer cell cultures. The transforming growth factor beta (TGFbeta) receptor inhibitor, LY2109761, that targets the signaling pathway of another top scoring hit, TGFbeta1, was synergistic with paclitaxel when used in combination on select breast cancer cell lines grown in 3D culture. We also determined the relative paclitaxel sensitivity of 22 TNBC cell lines and identified 18 drug-sensitive and four drug-resistant cell lines. Of significance, we found that both CCT007093 and mithramycin, when used in combination with paclitaxel, resulted in synergistic inhibition of the four paclitaxel-resistant TNBC cell lines.RNAi screening can identify druggable targets and novel drug combinations that can sensitize breast cancer cells to paclitaxel. This genomic-based approach can be applied to a multitude of tumor-derived cell lines and drug treatments to generate requisite pre-clinical data for new drug combination therapies to pursue in clinical investigations.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
Unknown unknown triple-receptor negative breast cancer not applicable LY2109761 + Paclitaxel Preclinical Actionable In a preclinical study, LY2109761 and Taxol (paclitaxel) worked synergistically to inhibit the growth of triple-receptor negative breast cancer cell lines in culture (PMID: 20576088). 20576088
Unknown unknown triple-receptor negative breast cancer no benefit CCT007093 Preclinical Actionable In a preclinical study, CCT007093 did not inhibit growth of triple-receptor negative breast cancer cell lines in culture (PMID: 20576088). 20576088
Unknown unknown triple-receptor negative breast cancer not applicable Paclitaxel + Plicamycin Preclinical Actionable In a preclinical study, Mithracin (plicamycin) and Taxol (paclitaxel) worked synergistically to inhibit the growth of triple-receptor negative breast cancer cell lines in culture (PMID: 20576088). 20576088
Unknown unknown triple-receptor negative breast cancer not applicable CCT007093 + Paclitaxel Preclinical Actionable In a preclinical study, CCT007093 and Taxol (paclitaxel) worked synergistically to inhibit growth of triple-receptor negative breast cancer cell lines in culture (PMID: 20576088). 20576088