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Lessons learned from the past: CDK4&6 inhibition over time

Angelo Di Leo

Speaker: Angelo Di Leo.

Duration: 23:17.

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Summary

Dr Angelo Di Leo focuses on preclinical data and the history of CDK4&6 inhibition. Endocrine therapy in breast cancer was first attempted – as radical mastectomy – in 1894; the first oophorectomy was performed in 1896. Then, constant progress in endocrine therapy for ER-positive breast cancer culminated, 50 years ago, in tamoxifen. The second half of the 1990s saw a new generation of endocrine therapy agents, the aromatase inhibitors, and trastuzumab – relevant to endocrine-sensitive disease because of its synergy with endocrine therapy. Next came fulvestrant, and then, for almost 10 years, nothing important – until final results on everolimus (from BOLERO-2) were published in 2012. Then, a major breakthrough came in 2015 with the CDK4&6 inhibitors. These drugs will have a substantial impact on the way we treat metastatic, ER-positive breast cancer. The cyclin D1 pathway plays a role in co-promoting the proliferation of luminal breast cancer by facilitating transitions between phases of the cell cycle. That other cyclins are also involved in this process may explain escape mechanisms of CDK4&6 inhibitors. The first-generation CDK inhibitors failed to reach the clinic because of poor specificity and drug-delivery problems, but the new generation of chemical CDK4&6 inhibitors (abemaciclib, palbociclib, and ribociclib) has reached the clinic. The different potencies of CDK4&6 inhibition by these three compounds may have implications for their activity and toxicity profiles.