Combined treatment with silibinin and epidermal growth factor receptor tyrosine kinase inhibitors overcomes drug resistance caused by T790M mutation.

Abstract

Although epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKI) produce an initially dramatic response in lung cancer patients harboring a mutation in the EGFR gene, development of acquired resistance is almost inevitable. A secondary mutation of threonine 790 (T790M) is associated with approximately half of the cases of acquired resistance. This study investigated whether the addition of silibinin to therapy with gefitinib or erlotinib could overcome T790M-mediated drug resistance considering that silibinin has various antitumor effects, including EGFR modulation. Silibinin selectively reduced the activity of the EGFR family (EGFR, ErbB2, and ErbB3) through the inhibition of receptor dimerization in lung cancer cells with EGFR mutations, but not in those harboring the wild type. In primary and acquired resistant cells with T790M, addition of silibinin enhanced the ability of EGFR-TKIs to downregulate EGFR signals and to inhibit cell growth. Similarly, the combination of silibinin and erlotinib effectively suppressed tumor growth in erlotinib resistance-bearing PC-9 xenografts. The results indicate that the addition of silibinin to EGFR-TKIs is a promising strategy to overcome T790M-mediated drug resistance.

• Authors: Jin Kyung Rho, Yun Jung Choi, Byung-Suk Jeon, Su Jin Choi, Gi Jeong Cheon, Sang-Keun Woo, Hye-Ryoun Kim, Cheol Hyeon Kim, Chang-Min Choi, Jae Cheol Lee
• Journal: Molecular cancer therapeutics (Mol Cancer Ther) Vol. 9 Issue 12 Pg. 3233-43 (Dec 2010) ISSN: 1538-8514 [Electronic] United States
• PMID: 21159609 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: ©2010 AACR.

Chemical References

• Protein Kinase Inhibitors
• Quinazolines
• Silymarin
• Tyrosine
• Silybin
• Erlotinib Hydrochloride
• ErbB Receptors

Topics

• Amino Acid Substitution (genetics)
• Animals
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Dose-Response Relationship, Drug
• Down-Regulation (drug effects)
• Drug Resistance, Neoplasm (drug effects)
• Drug Synergism
• ErbB Receptors (antagonists & inhibitors, genetics)
• Erlotinib Hydrochloride
• Humans
• Mice
• Mutation (genetics)
• Protein Kinase Inhibitors (pharmacology)
• Protein Multimerization (drug effects)
• Quinazolines (chemistry, pharmacology)
• Signal Transduction (drug effects)
• Silybin
• Silymarin (chemistry, pharmacology)
• Tyrosine (genetics)
• Xenograft Model Antitumor Assays