SMALL MOLECULE INHIBITORS IN EGFR/HER-2 AND MUTANT RAS/RAF BREAST CANCER MODEL SYSTEMS
Nagaria, Teddy S.
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Dysregulation of receptor tyrosine kinase (RTK) signaling has been implicated in the pathogenesis of breast cancer. Both EGFR and HER-2 regulate tumor cell proliferation and survival through the Ras-Raf-Mek-Erk (MAPK) pathway. Cyclin-dependent kinases (CDKs) are implicated in regulating proliferative and survival signaling downstream of the MAPK pathway. Here I show that CDK inhibitors exhibit an order-of-magnitude greater cytotoxic potency than a suite of inhibitors targeting RTK and Ras-MAPK signaling in cell lines representative of clinically recognized breast cancer subtypes. Drug combination studies showed that the pan CDK inhibitor, Flavopiridol, synergistically potentiated cytotoxicity induced by the Raf inhibitor, Sorafenib. In vivo mouse models of breast cancer treated with both drugs exhibited reduced primary tumor growth rates and metastatic tumor load in the lungs compared to treatment with either drug alone, and this correlated with greater reductions in Rb signaling and Mcl-1 expression in resected tumors. In addition, Mek inhibition with U0126 potentiated the cytotoxic efficacy of Sorafenib, showing added benefits of drug combination to reduce doses while achieving greater therapeutic efficacy in a mutant Ras/Raf triple-negative breast cancer cell line. In vivo mouse models showed targeted Raf (Sorafenib) and Mek (AZD6244) inhibition resulted in reduced primary tumor growth and metastatic tumor load in the lungs, with the combined targeted Raf and Mek treatment showing greater inhibition than targeting either Raf or Mek alone. Synergistic anti-tumorigenic effects of the Sorafenib-Flavopiridol and Sorafenib-U0126/AZD6244 combinations across breast cancer cells driven by EGFR/HER-2 or Ras-MAPK signaling suggest the broad applicability of these combinations to treat multiple breast cancer subtypes. These data highlight the significance of co-targeting Raf, Mek, and CDKs to effectively disrupt constitutive Ras-MAPK signaling that may give rise to resistance and metastasis.