Cyclacel's CYC065 CDK inhibitor demonstrates potential against breast cancer resistant to trastuzumab

Cyclacel Pharmaceuticals, Inc. (Nasdaq:CYCC) (Nasdaq:CYCCP) (Cyclacel or the Company), today announced the publication of preclinical data in the Proceedings of the National Academy of Sciences (PNAS), demonstrating that cyclin E plays a major role in making Human Epidermal growth factor Receptor 2 positive (HER2+) breast cancer resistant to trastuzumab (Herceptin®), a widely used medicine for breast cancer patients who test positive for HER2. The publication provides a rationale for exploring Cyclacel's orally available CDK inhibitors in this patient population.

Elevated expression levels of cyclin E in HER2+ patients treated with trastuzumab resulted in a reduced rate of clinical benefit and lower survival compared with patients whose cancers did not overexpress cyclin E. Treatment of HER2+ breast cancer cells resistant to trastuzumab with CYC065, Cyclacel's cyclin-dependent kinase (CDK) inhibitor, blocked CDK2/cyclin E activity, dramatically slowed tumor growth and killed resistant breast cancer cells. 

"For over a decade Cyclacel has emerged as a leader in the study of cell cycle biology and the identification of novel anticancer drugs that exploit mechanisms of cell cycle control.  We are excited about CYC065's promising activity in breast cancer resistant to trastuzumab, one of the mainstay therapies for early-stage breast cancer," said Spiro Rombotis, Cyclacel's President & Chief Executive Officer. "The publication by a leading breast cancer group extends and supports previous reports showing that targeting CDK2/cyclin E with Cyclacel's novel CDK inhibitors, seliciclib and CYC065, can kill cancer cells, such as breast and lung cancer, that fail to respond to current standards of care."

The CDK2 enzyme and its partner protein, cyclin E, have been extensively investigated as therapeutic targets in light of their frequent deregulation in breast cancers with a poor prognosis. In the PNAS article titled "Cyclin E amplification/overexpression is a mechanism of trastuzumab resistance in HER2 positive breast cancer patients," investigators from Massachusetts General Hospital Cancer Center, (Boston, MA), Vall d'Hebron University Hospital (Barcelona, Spain), Memorial Sloan-Kettering Cancer Center (New York, NY) and Manitoba Institute of Cell Biology (Winnipeg, Canada) performed a genome-wide analysis to pinpoint causes of resistance in HER2+ breast cancer. Their analysis identified cyclin E as the common genetic signature of resistance to trastuzumab in HER2+ breast cancer cells.  Cyclacel's CYC065, a second generation CDK inhibitor, was found to be effective in killing trastuzumab-resistant breast cancer cells in vitro and in vivo. The mechanism of action of CYC065 included inhibition of CDK2/cyclin E, cell cycle arrest and induction of cell death by apoptosis.

"We have determined that breast cancer cells resistant to therapeutic agents targeting HER2 are highly sensitive to CDK inhibition by CYC065," said Maurizio Scaltriti, Ph.D., research scientist from the Division of Hematology and Oncology of the Massachusetts General Hospital Cancer Center, and first author of the manuscript. "Amplification and overexpression of cyclin E is a mechanism by which breast cancer cells develop resistance to trastuzumab. Modulations of cyclin E levels by genetic means result in different sensitivity towards the anti-HER2 agent. Cyclin E overexpressing, trastuzumab-resistant cells have higher CDK2 activity and are more sensitive to pharmacological inhibition by inhibitors, such as seliciclib or its more potent derivative, CYC065. CYC065 has promising in vivo activity in xenograft models of resistant cells, and this activity appears to be enhanced by the addition of trastuzumab."

An estimated 15 to 20 percent of breast cancers have an amplification of the HER2/neu gene or overexpression of its protein product, which results in an aggressive tumor phenotype and reduced survival. HER2 targeted agents such as trastuzumab are highly effective in adjuvant and metastatic breast cancer. However clinical effectiveness is strongly diminished by primary or acquired resistance. Identification and targeting the causative mechanisms for such resistance, such as CDK2/cyclin E activation, may have a significant impact in improving therapeutic outcomes in HER2+ breast cancer patients. In a small retrospective study the authors of the PNAS article demonstrated that approximately 35% of HER2+ breast tumors had overexpressed/amplified cyclin E and this correlated with decreased sensitivity to trastuzumab. Frequently, cyclin E overexpression was not associated with other mechanisms of trastuzumab resistance underscoring the potential contribution that CDK inhibitors, such as CYC065 and seliciclib, may confer in this patient population.

Cyclacel continues to collaborate with the scientific team led by Jose Baselga, M.D., Ph.D., Chief of the Division of Hematology/Oncology and Associate Director of the Massachusetts General Hospital Cancer Center in order to further validate the therapeutic potential of CDK inhibitors in a cyclin E-mediated, trastuzumab-resistant patient population.

SOURCE Cyclacel Pharmaceuticals, Inc.