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Epidermal Growth Factor Receptor Expression Is a Candidate Target of the Synergistic Combination of Trastuzumab and Flavopiridol in Breast Cancer¹

Massachusetts General Hospital Cancer Center, Charlestown, Massachusetts 02129 [R. N., S. T., C. Y., E. V. S.], and The Pediatric Service, Massachusetts General Hospital, Boston, Massachusetts 02114 [E. V. S.]

ErbB2 and cyclin D1 are interacting oncogenes that are particularly important in breast cancer. We demonstrated previously synergy between two drugs that separately address each oncogene, trastuzumab and flavopiridol. Here we examine the cellular basis for this interaction. Although both drugs are thought to alter cell cycle progression, the combination of trastuzumab and flavopiridol had little effect on G₁ progression or retinoblastoma protein phosphorylation. Instead, trastuzumab-flavopiridol synergistically enhanced apoptosis. Recent data have suggested that transcription elongation mediated by Cdk9 in P-TEFb is a more sensitive flavopiridol target than Cdk4. Supporting this view, we found synergy between 5,6-dichloro-1-ß-D-ribofuranosylbenzimidazole riboside and trastuzumab, but not between inhibitors of Cdk4 and trastuzumab. Similarly, a signature set of mRNAs that included the epidermal growth factor receptor (EGFR) responded to the combination of trastuzumab-flavopiridol in a gene expression array analysis. Three lines of evidence confirmed the EGFR is a potential target of flavopiridol-trastuzumab synergy: (a) EGFR protein expression was rapidly and completely lost after combination treatment; (b) a cell line that expresses amplified levels of both erbB2 and the EGFR was resistant to the combined drugs; and (c) treatment with epidermal growth factor prevented any therapeutic effects of flavopiridol and trastuzumab, singly or in combination. Taken together, our results suggest that synergy between flavopiridol and trastuzumab can result from enhanced apoptosis, and that combination effects on EGFR expression are involved in the interaction.

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