Approximately 20% of breast cancers overexpress oncogenic tyrosine kinase receptor HER2/NEU. Patients with metastatic HER2+ cancer typically receive HER2-targeting monoclonal antibodies, trastuzumab and pertuzumab (often combined with a taxane); a small-molecule HER2 inhibitor lapatinib or a HER2-specific antibody-drug conjugate T-DM1 are used in later arms of treatment. Despite the transformative effect of HER2- targeting drugs in the adjuvant setting, nearly 70% of patients with metastatic HER2+ breast cancer have intrinsic resistance and nearly all become resistant to HER2-targeting therapy after initial response. There is a clear need for an agent that, when combined with HER2-targeting drugs, would overcome or prevent resistance to such drugs. We have developed highly selective and non-toxic inhibitors of cyclin-dependent kinase 8 (CDK8) and its paralog CDK19, which, unlike better-known members of the CDK family, regulate transcription but not cell cycle progression. Higher CDK8 expression is associated with a shorter relapse-free and distant metastasis-free survival in HER2+ patients. We have found that Senexin B, CDK8/19 inhibitor drug candidate, has a strong synergistic effect with different classes of HER2-targeting agents in all the tested HER2+ breast cancer cell lines and overcomes both inherent and acquired resistance to such drugs. Furthermore, combining Senexin B with HER2-targeting drugs suppressed the development of drug resistance. Synergistic inhibition of phosphorylation of two transcription factors implicated in breast cancer has been identified as a putative mechanism of synergy between CDK8- and HER2-targeting drugs. We now propose to develop a therapeutic strategy combining CDK8/19- and HER2- targeting drugs for the treatment of metastatic HER2+ breast cancer.
In Aim 1, we will investigate whether Senexin B potentiates the effect of the trastuzumab/pertuzumab (T+P) combination, the current first line standard-of-care for HER2+ breast cancers, in vitro and in vivo, and whether Senexin B prevents the development of resistance to T+P.
In Aim 2, we will test if cells selected for acquired T+P resistance and T+P treated tumors overexpress CDK8, as a possible patient selection criterion for the initial clinical development. We will also determine if treatment with T+P combined with Senexin B, in vitro and in vivo, decreases the phosphorylation of HER2- and CDK8-regulated transcription factors, as potential markers of treatment response. The anticipated Phase II SBIR program will include preclinical dose regimen optimization, extension of synergy studies to other drug combinations, optimization of the marker assays, and initiation of a Phase I clinical trial of a combination of Senexin B with HER2-targeting therapies. We hope that the use of CDK8/19 inhibitors will have a transformative effect on the long-term survival of patients with metastatic HER2+ breast cancer.
Approximately 20% of breast cancers are characterized as HER2-positive, and patients with such cancers are treated with HER2-targeting drugs (such as Herceptin). Although HER2-targeting drugs given after surgery drastically decrease tumor recurrence, nearly 70% of patients with metastatic HER2-positive breast cancer do not respond to HER2-targeting therapy and almost all of the initially responsive cancers eventually become resistant. We have found that a non-toxic drug acting on proteins called CDK8/19 overcomes resistance to HER2-targeting drugs and prevents such resistance from developing; we now propose a program of studies that will lead to combining this drug with HER2-targeting therapies in the treatment of patients with metastatic HER2-positive breast cancer.
