Abstract
Simple SummarySelective killing of cancer cells is privileged mainstream in cancer treatment and targeted therapy represents the new tool with a potential to pursue this aim. It can also aid to overcome resistance of conventional chemo- or radio-therapy. Common mutations of cancer cells (defective G1 control) favor inhibiting intra-S and G2/M-checkpoints, which are regulated by ATR–CHK1–WEE1 pathway. The ATR–CHK1–WEE1 axis has produced several clinical candidates currently undergoing clinical trials in phase II. Clinical results from randomized trials by ATR and WEE1 inhibitors warrant ongoing clinical trials in phase III.Selective killing of cancer cells while sparing healthy ones is the principle of the perfect cancer treatment and the primary aim of many oncologists, molecular biologists, and medicinal chemists. To achieve this goal, it is crucial to understand the molecular mechanisms that distinguish cancer cells from healthy ones. Accordingly, several clinical candidates that use particular mutations in cell-cycle progressions have been developed to kill cancer cells. As the majority of cancer cells have defects in G1 control, targeting the subsequent intra‑S or G2/M checkpoints has also been extensively pursued. This review focuses on clinical candidates that target the kinases involved in intra‑S and G2/M checkpoints, namely, ATR, CHK1, and WEE1 inhibitors. It provides insight into their current status and future perspectives for anticancer treatment. Overall, even though CHK1 inhibitors are still far from clinical establishment, promising accomplishments with ATR and WEE1 inhibitors in phase II trials present a positive outlook for patient survival.
Highlights
Cancer cells demonstrate characteristics such as sustained proliferative signaling, evading growth suppressors, resisting cell death, induced angiogenesis, activated invasion and metastasis, enabled replicative immortality, deregulated cellular energetics, avoiding immune destruction, genome instability and mutation, and tumor-promoting inflammation, which make it difficult to cure [1]
We reviewed recently presented results from clinical trials to provide insight into their perspectives for anticancer treatment
The ATR–CHK1–WEE1 axis is highly implicated in cancer-cell processing as these cells are under constant replication stress (RS) with various defects hampering DNA repair
Summary
Cancer cells demonstrate characteristics such as sustained proliferative signaling, evading growth suppressors, resisting cell death, induced angiogenesis, activated invasion and metastasis, enabled replicative immortality, deregulated cellular energetics, avoiding immune destruction, genome instability and mutation, and tumor-promoting inflammation, which make it difficult to cure [1] Each of these hallmarks provides an opportunity to design specific treatments and agents that can target cancer cells more selectively than conventional chemotherapy. Cell-cycle progression needs to be tightly regulated by checkpoints assuring that damaged DNA is repaired correctly, and that DNA replication is completed before entering mitosis Failure in this can lead to cell death or accelerate mutagenesis to induce tumor formation [8,9,10]. We reviewed recently presented results from clinical trials to provide insight into their perspectives for anticancer treatment
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