Vuina, Karla; (2024) Understanding the anti-cancer efficacy of cyclin-dependent kinase inhibitors. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Tumour growth is driven by sustained cellular growth and proliferation. The key regulator of cellular proliferation is the activity of cyclin-dependent kinases (CDKs). An increased CDK activity has been widely reported in cancer. Therefore, CDK inhibitors (CDKis) carry great potential as pan-cancer therapies. Multiple CDKis have been in development, with three CDK4/6is being the most successful and already in clinical use for treating advanced breast cancer. Moreover, a selective CDK7i, samuraciclib, has been fast-tracked for clinical approval in treating CDK4/6i-resistant cancers. CDK4/6 have an important role in promoting the G1-to-S transition, and CDK7 has a central role in activating all mitotic CDKs and regulating RNA polymerase II-mediated transcription. However, the exact mechanisms underlying cancer cell sensitivity to these CDKis are not well understood. Here I show that samuraciclib, the most clinically advanced CDK7i, as well as the CDK4/6i palbociclib, induce senescent phenotypes without promoting cell death. My work reveals that active growth signalling, via mTOR pathway, increases cell size during a CDKi arrest, which is an important driver of senescence. Even when cells do not permanently arrest during a CDKi arrest, an excessive increase in cell size causes replication-acquired damage and subsequent cell cycle exit. Since enhanced growth signalling is a hallmark of cancer, this could help explain the anti-cancer efficacy of these CDKis. Moreover, I show that samuraciclib induces a more robust cell cycle exit and a more rapid accumulation of p21 compared to palbociclib. I show that samuraciclib-induced cell cycle arrest and the induction of a senescent state relies on active p53-dependent upregulation of p21. However, samuraciclib sensitivity does not depend on the tumour suppressor Rb, whereas palbociclib sensitivity does. This work therefore gives insight into mechanisms by which these two clinically relevant CDKis achieve their anti-cancer efficacy and reveals differences in their sensitivity and resistance mechanisms.

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