Dual inhibition of EGFR and MET induces synthetic lethality in triple-negative breast cancer cells through downregulation of ribosomal protein S6.

Abstract

Triple-negative breast cancer (TNBC) exhibits innate resistance to the EGFR inhibition despite high level expression of EGFR. Recently, we found that the proliferation of basal-like (BL) subtype TNBC cells is synergistically inhibited by combination of EGFR and PI3K/AKT inhibitors. On the contrary, TNBC cells of mesenchymal stem-like (MSL) subtype are resistant to these combinations. To identify potential synthetic lethal interaction of compounds for treatment of MSL subtype TNBC cells, we performed MTT screening of MDA-MB‑231 cells with a small library of receptor tyrosine kinase inhibitors (RTKIs) in the presence of gefitinib, an EGFR inhibitor. We identified MET inhibitors as potent RTKIs that caused synthetic lethality in combination with gefitinib in MDA-MB‑231 cells. We demonstrated that combination of a MET inhibitor SU11274 with various EGFR inhibitors resulted in synergistic suppression of cell viability (in MTT assay) and cell survival (in colony formation assay) of MSL subtype TNBC cells. We further demonstrated that SU11274 alone induced G2 arrest and gefitinib/SU11274 combination sustained the SU11274-induced G2 arrest in these cells. In addition, SU11274/gefitinib combination synergistically reduced the level of ribosomal protein S6 (RPS6) in MSL subtype TNBC cells. In addition, knockdown of RPS6 itself, in both HS578T and MDA-MB‑231, markedly reduced the proliferation of these cells. Taken together, our data suggest that dual targeting of EGFR and MET inhibits the proliferation of MSL subtype TNBC cells through downregulation of RPS6.

• Authors: Yong Weon Yi, Kyusic You, Edward Jeong Bae, Sahng-June Kwak, Yeon-Sun Seong, Insoo Bae
• Journal: International journal of oncology (Int J Oncol) Vol. 47 Issue 1 Pg. 122-32 (Jul 2015) ISSN: 1791-2423 [Electronic] Greece
• PMID: 25955731 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• ((3Z)-N-(3-chlorophenyl)-3-((3,5-dimethyl-4-((4-methylpiperazin-1-yl)carbonyl)-1H-pyrrol-2-yl)methylene)-N-methyl-2-oxo-2,3-dihydro-1H-indole-5-sulfonamide)
• Indoles
• Peptide Library
• Piperazines
• Quinazolines
• Ribosomal Protein S6
• Sulfonamides
• EGFR protein, human
• ErbB Receptors
• MET protein, human
• Proto-Oncogene Proteins c-met
• Gefitinib

Topics

• Cell Line, Tumor
• Cell Survival (drug effects)
• Down-Regulation
• Drug Synergism
• ErbB Receptors (antagonists & inhibitors)
• Female
• Gefitinib
• Humans
• Indoles (pharmacology)
• Peptide Library
• Piperazines (pharmacology)
• Proto-Oncogene Proteins c-met (antagonists & inhibitors)
• Quinazolines (pharmacology)
• Ribosomal Protein S6 (metabolism)
• Sulfonamides (pharmacology)
• Triple Negative Breast Neoplasms (drug therapy, metabolism)