Overcoming Resistance To Her2-Targeting Drugs Using Cdk8 Inhibitors

Proceedings: AACR 106th Annual Meeting 2015; April 18-22, 2015; Philadelphia, PAHER2-targeting therapies transformed the treatment of patients with HER2+ breast cancer and are now being explored in other cancer types. However, nearly 70% of patients with HER2+ metastatic breast cancer have intrinsic resistance and almost all develop acquired resistance to HER2-targeting drugs. New therapeutic approaches aimed at resistance to HER2-targeting therapies are urgently needed. We have previously found that resistance to HER2-targeting drugs involves increased activity of the phosphatase PP2A. PP2A was reported to stimulate the kinase activity of CDK8, a transcription-regulating kinase that in contrast to some other members of the CDK family does not regulate cell cycle progression. Thus CDK8 may play a role in resistance to HER2-targeting therapies. CDK8 has been identified as an oncogene amplified in 50% of colon cancers. Immunohistochemical staining of breast tissue arrays and meta-analysis of breast cancer microarray data revealed that CDK8 is overexpressed in breast cancers and that higher CDK8 expression correlates with the failure of systemic therapy. Selective small-molecule inhibitors of CDK8 and its paralog CDK19 show no limiting toxicities at therapeutically effective doses. We have found that an optimized CDK8/19 inhibitor Senexin B has a synergistic growth-inhibitory effect in combinations with an anti-HER2 monoclonal antibody (a biosimilar of trastuzumab) and with the HER2/EGFR small-molecule inhibitor lapatinib. These synergistic effects were observed in all HER2+ breast and colon cancer cell lines tested so far, including those that are either sensitive to HER2-targeting drugs or non-responsive to these agents due to innate or acquired resistance. Furthermore, combining lapatinib with Senexin B inhibited the development of de novo resistance to lapatinib. Taken together these results suggest that combining anti-HER2 and anti-CDK8 therapies is a rational potential treatment for HER2+ cancers, which may overcome both innate and acquired resistance to HER2-targeting drugs.Citation Format: Martina McDermott, Laura Ivers, Norma Ou0027Donovan, John Crown, Igor Roninson, Eugenia V. Broude. Overcoming resistance to HER2-targeting drugs using CDK8 inhibitors. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5459. doi:10.1158/1538-7445.AM2015-5459