Targeting cell cycle regulation via the G2-M checkpoint for synthetic lethality in melanoma

Abstract

Disruption of cell cycle checkpoints has been well established as a hallmark of cancer. In particular, the G1-S transition mediated by the cyclin D-cyclin-dependent kinase 4/6 (CDK4/6) pathway is dysregulated in more than 90% of melanoma cases. Therefore, tumor cells mainly rely on the G2-M checkpoint to halt the cell cycle in order to repair DNA damage. Here, we review the promising method of cell cycle-mediated synthetic lethality for melanoma treatment, which entails exploiting somatically acquired mutations in the G1-S transition with inhibitors of the G2-M transition in order to specifically kill melanoma cells. The idea stems from the theory that melanoma cells lacking G1-S checkpoints are particularly vulnerable to mitotic catastrophe when presented with G2-M checkpoint inhibition in addition to DNA damage, whereas normal cells with intact G1-S checkpoints should theoretically be spared. This review explores the link between cell cycle dysregulation and synthetic lethality in melanoma cells and discusses potential future applications for this treatment.

Keywords: CHK1; G1-S transition; G2-M transition; WEE1; cell cycle checkpoint; melanoma; synthetic lethality.

Figure 1.

Achieving synthetic lethality by abrogating the G2-M checkpoint in G1-S checkpoint-deficient melanoma cells. (A) G2-M cell cycle transition is mediated by CHK1, MK2, WEE1, and HDACs in a normal cell. (B) G1-S checkpoint-defective melanoma cells can be targeted by several potential avenues for therapeutic inhibition (dashed inhibition lines). These cells progress uninhibited through the cell cycle and experience mitotic catastrophe. Thickness of arrows and inhibition lines represents relative pathway activity

Figure 2.

Chemical structures of G2-M checkpoint inhibitors. 2D structures available from PubChem (https://pubchem.ncbi.nlm.nih.gov) are provided for CHK1 inhibitors, UCN-01 (CID 72271), PF-00477736 (CID 135565545), AZD7762 (CID 11152667), MK-8776 (CID 16224745), GDC-0575 (CID 46917793), prexasertib (CID 46700756); WEE1 inhibitors, PD0166285 (CID 5311382) and adavosertib (CID 24856436); p38 MAPK inhibitor ralimetinib (CID 11539025); and HDAC inhibitor azelaic bishydroxamic acid (CID 65268). All CHK1, WEE1, and p38 MAPK inhibitors function as ATP competitive small-molecule inhibitors