Abstract MS1-1: Beyond CDK 4/6: Targeting additional cell cycle and transcriptional CDKs in breast cancer

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Abstract Cyclin-dependent kinases (CDKs) are critical regulators of cell cycle progression and RNA transcription. The cell cycle CDKs 4, 6, 2 and 1 are core components of the cell cycle machinery and govern transition between cell cycle phases. The transcriptional CDKs, including CDKs 7, 9 and 12, phosphorylate the C-terminal domain (CTD) of RNA polymerase II and regulate transcriptional initiation, elongation and processing. Compounds in clinical trial include the selective CDK4/6 inhibitors, as well as less selective agents that target CDKs 1 and 2 and the transcriptional CDKs. The success of selective CDK4/6 inhibitors in HR-positive breast cancer has validated these cell cycle kinases as anticancer drug targets. Resistance to CDK4/6 inhibition may in part be mediated by elevated levels of cyclin E-CDK2 activity (also a mechanism of acquired trastuzumab resistance in HER2+ disease). To this end, drugs with potent CDK2 inhibitory are in development, including BAY1000394 and CYC-065. High cyclin E-CDK2 activity has also been described in triple-negative breast cancer (TNBC) and associated stem cells, where such agents also have potential efficacy. CDK1 may also be an important target in MYC-overexpressing TNBC, where a synthetic lethal interaction has been described. Recently, mechanisms by which CDKs interact with DNA damage and DNA repair pathways have been examined. For example, CDK1 is required for efficient recruitment of BRCA1 to sites of DNA damage. Consequently, CDK1 inhibition disrupts homologous recombination (HR) repair, resulting in sensitization of HR-proficient TNBCs to PARP inhibition. Additionally, CDK12 governs the transcriptional elongation and processing of a large number of HR pathway genes. Considering the complex mechanisms by which BRCA-deficient cells may restore HR to escape PARP inhibitors, the simultaneous suppression of multiple HR genes by CDK12 inhibition together with PARP inhibition may be an attractive strategy for re-sensitizing cells to these agents. Dinaciclib, a known inhibitor of CDKs 1, 2, 5 and 9, also has highly potent CDK12 inhibitory activity. In TNBC cells, dinaciclib reduces phosphorylation of the RNA pol II CTD and represses expression of a subset of DNA damage response and repair genes that mimics CDK12 depletion. Dinaciclib compromises HR, sensitizes HR-proficient cells to PARP inhibition and also reverses both acquired and de novo PARP inhibitor resistance in BRCA1 mutated TNBC cell line and patient-derived xenograft (PDX) models mediated by restored and residual HR, respectively. Additionally, in an HR-deficient PDX model displaying susceptibility to PARP inhibitor monotherapy, dinaciclib converts prolonged tumor growth inhibition to sustained regression. Finally, there has been renewed interest in CDK7, inhibition of which represses the expression of genes associated with superenhancers that define the oncogenic state. An Achilles cluster of such genes has been identified in TNBC, and cell line and PDX models have been shown to be highly susceptible to THZ1, a novel, covalent CDK7 inhibitor compound. In summary, emerging data implicate multiple CDK family members as relevant breast cancer drug targets with both monotherapy and combinatorial strategies under active development. Citation Format: Shapiro G. Beyond CDK 4/6: Targeting additional cell cycle and transcriptional CDKs in breast cancer. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr MS1-1.