Cell cycle checkpoint in cancer: a therapeutically targetable double-edged sword

Abstract

Major currently used anticancer therapeutics either directly damage DNA or target and upset basic cell division mechanisms like DNA replication and chromosome segregation. These insults elicit activation of cell cycle checkpoints, safeguard mechanisms that cells implement to correctly complete cell cycle phases, repair damage or eventually commit suicide in case damage is unrepairable. Although cancer cells appear to be advantageously defective in some aspects of checkpoint physiology, recent acquisitions on the biochemical mechanisms of the various checkpoints are offering new therapeutic approaches against cancer. Indeed, chemical manipulation of these mechanisms is providing new therapeutic strategies and tools to increase the killing efficacy of major cancer therapeutics as well as to directly promote cancer cell death. In this review we summarize developing concepts on how targeting cell cycle checkpoints may provide substantial improvement to cancer therapy.

Keywords: Cancer drug; Cell cycle checkpoint; Chk1; DNA damage; Fcp1; Mitosis; Spindle assembly checkpoint; Taxane; Vinca alkaloids; Wee1.

Fig. 1

Targeting the cell cycle checkpoints in cancer. a Chk1/2 or ATR inhibitors in combination with DNA damaging drugs forces cancer cells with DNA damage to bypass the S and G2/M checkpoint arrest and enter mitosis, leading to cell death. b Wee1 inhibitors in combination with DNA damaging drugs forces cancer cells with DNA damage to bypass the G2/M checkpoint arrest and progress into mitosis, leading to cell death. c Wee1 inhibitors sustain the SAC-dependent mitotic delay induced by AMCDs, substantially increasing AMCDs therapeutic efficacy