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Clinical Candidates Targeting the ATR-CHK1-WEE1 Axis in Cancer.

ABSTRACT: 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.

SUBMITTER: Gorecki L

PROVIDER: S-EPMC7918546 | biostudies-literature | 2021 Feb

REPOSITORIES: biostudies-literature

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Clinical Candidates Targeting the ATR-CHK1-WEE1 Axis in Cancer.

Gorecki Lukas L Andrs Martin M Korabecny Jan J

Cancers 20210214 4

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 de ...[more]

PMID: 33672884

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Pharmacological targeting the ATR-CHK1-WEE1 axis involves balancing cell growth stimulation and apoptosis.

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Targeting the ATR-CHK1 Axis in Cancer Therapy.

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Targeting the ATR/CHK1 Axis with PARP Inhibition Results in Tumor Regression in <i>BRCA</i>-Mutant Ovarian Cancer Models.

Project description:Purpose: PARP inhibition (PARPi) has modest clinical activity in recurrent BRCA-mutant (BRCAMUT) high-grade serous ovarian cancers (HGSOC). We hypothesized that PARPi increases dependence on ATR/CHK1 such that combination PARPi with ATR/CHK1 blockade results in increased cell death and tumor regression.Experimental Design: Effects of PARPi (olaparib), CHK1 inhibition (CHK1i;MK8776), or ATR inhibition (ATRi;AZD6738) alone or in combination on survival, colony formation, cell cycle, genome instability, and apoptosis were evaluated in BRCA1/2MUT HGSOC cells. Tumor growth in vivo was evaluated using a BRCA2MUT patient-derived xenograft (PDX) model.Results: PARPi monotherapy resulted in a decrease in BRCAMUT cell survival, colony formation and suppressed but did not eliminate tumor growth at the maximum tolerated dose (MTD) in a BRCA2MUT PDX. PARPi treatment increased pATR and pCHK1, indicating activation of the ATR-CHK1 fork protection pathway is relied upon for genome stability under PARPi. Indeed, combination of ATRi or CHK1i with PARPi synergistically decreased survival and colony formation compared with single-agent treatments in BRCAMUT cells. Notably, PARPi led to G2 phase accumulation, and the addition of ATRi or CHK1i released cells from G2 causing premature mitotic entry with increased chromosomal aberrations and apoptosis. Moreover, the combinations of PARPi with ATRi or CHK1i were synergistic in causing tumor suppression in a BRCA2MUT PDX with the PARPi-ATRi combination inducing tumor regression and in most cases, complete remission.Conclusions: PARPi causes increased reliance on ATR/CHK1 for genome stability, and combination PARPi with ATR/CHK1i is more effective than PARPi alone in reducing tumor burden in BRCAMUT models. Clin Cancer Res; 23(12); 3097-108. ©2016 AACR.

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Overexpression of TopBP1, a canonical ATR/Chk1 activator, paradoxically hinders ATR/Chk1 activation in cancer.

Project description:Topoisomerase IIβ-binding protein 1 (TopBP1) is involved in cellular replication among other functions and is known to activate ATR/Chk1 during replicative stress. TopBP1 is also expressed at high levels in many cancers. However, the impact of TopBP1 overexpression on ATR/Chk1 activation and cancer development has not been investigated. Here we demonstrate that the degree of ATR/Chk1 activation is regulated by TopBP1 in a biphasic, concentration-dependent manner in a nontransformed MCF10A cell line and several cancer cell lines, including H1299, MDA-MB468, and U2OS. At low levels, TopBP1 activates ATR/Chk1, but once TopBP1 protein accumulates above an optimal level, it paradoxically leads to lower activation of ATR/Chk1. This is due to the perturbation of ATR-TopBP1 interaction and ATR chromatin loading by excessive TopBP1. Overexpression of TopBP1 thus hinders the ATR/Chk1 checkpoint response, leading to the impairment of genome integrity as demonstrated by the cytokinesis-block micronucleus assay. In contrast, moderate depletion of TopBP1 by shRNA in TopBP1-overexpressing cancer cells enhanced ATR/Chk1 activation and S-phase checkpoint response after replicative stress. The clinical significance of these findings is supported by an association between TopBP1 overexpression and genome instability in many types of human cancer. Taken together, our study illustrates an unexpected relationship between the levels of TopBP1 and the final functional outcome and suggests TopBP1 overexpression as a new mechanism directly contributing to genomic instability during tumorigenesis.

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