Checkpoint Kinase 1 Inhibition Enhances Cisplatin Cytotoxicity and Overcomes Cisplatin Resistance in SCLC by Promoting Mitotic Cell Death

Hsu, Wei‐Hsun; Zhao, Xiaoliang; Zhu, Jianquan; Kim, In Kyu; Rao, Guanhua; McCutcheon, Justine N.; Hsu, Shuo-Tse; Teicher, Beverly A.; Kallakury, Bhaskar; Dowlati, Afshin; Zhang, Kun; Giaccone, Giuseppe

doi:10.1016/j.jtho.2019.01.028

Cited by 43 publications

(34 citation statements)

References 56 publications

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“…This fact indicates the heterogeneous nature of cancer, which is reiterated, as recently demonstrated, in cell lines [26]. Importantly, our results show that the CHK1 inhibitor, rabusertib was able to overcome resistance to cisplatin in a resistant model of breast cancer, suggesting its potential use in combination in patients presenting with resistance to platinum agents [27].…”

Section: Discussionsupporting

confidence: 77%

Checkpoint Kinase 1 Pharmacological Inhibition Synergizes with DNA-Damaging Agents and Overcomes Platinum Resistance in Basal-Like Breast Cancer

Nieto-Jiménez

Alcaráz-Sanabria

Martínez-Canales

et al. 2020

IJMS

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Basal-like breast cancer is an incurable disease with limited therapeutic options, mainly due to the frequent development of anti-cancer drug resistance. Therefore, identification of druggable targets to improve current therapies and overcome these resistances is a major goal. Targeting DNA repair mechanisms has reached the clinical setting and several strategies, like the inhibition of the CHK1 kinase, are currently in clinical development. Here, using a panel of basal-like cancer cell lines, we explored the synergistic interactions of CHK1 inhibitors (rabusertib and SAR020106) with approved therapies in breast cancer and evaluated their potential to overcome resistance. We identified a synergistic action of these inhibitors with agents that produce DNA damage, like platinum compounds, gemcitabine, and the PARP inhibitor olaparib. Our results demonstrated that the combination of rabusertib with these chemotherapies also has a synergistic impact on tumor initiation, invasion capabilities, and apoptosis in vitro. We also revealed a biochemical effect on DNA damage and caspase-dependent apoptosis pathways through the phosphorylation of H2AX, the degradation of full-length PARP, and the increase of caspases 3 and 8 activity. This agent also demonstrated synergistic activity in a platinum-resistant cell line, inducing an increase in cell death in response to cisplatin only when combined with rabusertib, while no toxic effect was found on non-tumorigenic breast tissue-derived cell lines. Lastly, the combination of CHK1 inhibitor with cisplatin and gemcitabine resulted in more activity than single or double combinations, leading to a higher apoptotic effect. In conclusion, in our study we identify therapeutic options for the clinical development of CHK1 inhibitors, and confirm that the inhibition of this kinase can overcome acquired resistance to cisplatin.

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Section: Discussionsupporting

confidence: 77%

Checkpoint Kinase 1 Pharmacological Inhibition Synergizes with DNA-Damaging Agents and Overcomes Platinum Resistance in Basal-Like Breast Cancer

Nieto-Jiménez

Alcaráz-Sanabria

Martínez-Canales

et al. 2020

IJMS

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“…are common and compromise the efficacy of chemotherapy for lung cancer (8)(9)(10)(11). The mechanism of action of cisplatin relies on the induction of DNA damage (12), resulting in cell cycle arrest and subsequent apoptosis.…”

Section: Cdkn1a Upregulation and Cisplatin-pemetrexed Resistance In Nmentioning

confidence: 99%

CDKN1A upregulation and cisplatin‑pemetrexed resistance in non‑small cell lung cancer cells

et al. 2020

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Cisplatin-pemetrexed is a frequently adopted first-line treatment for patients with advanced non-small cell lung cancer (NSCLC) ineligible for biological therapy, notwithstanding its limited efficacy. In the present study, the RAL cell line, an epidermal growth factor receptor (EGFR)-wild-type, p53-and KRAS-mutated model of NSCLC, was used to investigate novel biomarkers of resistance to this treatment. Cells were analyzed 96 h (96 h-post wo) and 21 days (21 days-post wo) after the combined treatment washout. Following an initial moderate sensitivity to the treatment, the cell growth proliferative capability had fully recovered. Gene expression analysis of the resistant surviving cells revealed a significant upregulation of CDKN1A expression in the cells at 96-h post-wo and, although to a lesser extent, in the cells at 21 days-post wo, accompanied by an enrichment of acetylated histone H3 in its promoter region. CDKN1A was also upregulated at the protein level, being mainly detected in the cytoplasm of the cells at 96 h-post wo. A marked increase in the number of apoptotic cells, together with a significant G1 phase block, were observed at 96-h post wo in the cells in which CDKN1A was knocked down, suggesting its involvement in the modulation of the response of RAL cells to the drug combination. On the whole, these data suggest that CDKN1A plays a role in the response to the cisplatin-pemetrexed combination in advanced KRAS-mutated NSCLC, thus suggesting that it may be used as a promising predictive marker.

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“…In 2015 LY2606368, a specific CHK1 inhibitor with strong single-agent activity in vitro and in vivo was discovered (Refs 159–162). It demonstrated synergy with PARP inhibitors olaparib and BMN673 in ovarian and gastric cancer, respectively (Refs 163, 164) and potentiated cisplatin even in a panel of platinum-resistant human cancers cell lines (Refs 161, 165).…”

Section: Introductionmentioning

confidence: 99%

DNA damage checkpoint kinases in cancer

Smith

Southgate

Tweddle

et al. 2020

Expert Rev. Mol. Med.

182

168

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DNA damage response (DDR) pathway prevents high level endogenous and environmental DNA damage being replicated and passed on to the next generation of cells via an orchestrated and integrated network of cell cycle checkpoint signalling and DNA repair pathways. Depending on the type of damage, and where in the cell cycle it occurs different pathways are involved, with the ATM-CHK2-p53 pathway controlling the G1 checkpoint or ATR-CHK1-Wee1 pathway controlling the S and G2/M checkpoints. Loss of G1 checkpoint control is common in cancer through TP53, ATM mutations, Rb loss or cyclin E overexpression, providing a stronger rationale for targeting the S/G2 checkpoints. This review will focus on the ATM-CHK2-p53-p21 pathway and the ATR-CHK1-WEE1 pathway and ongoing efforts to target these pathways for patient benefit.

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Checkpoint Kinase 1 Inhibition Enhances Cisplatin Cytotoxicity and Overcomes Cisplatin Resistance in SCLC by Promoting Mitotic Cell Death

Cited by 43 publications

References 56 publications

Checkpoint Kinase 1 Pharmacological Inhibition Synergizes with DNA-Damaging Agents and Overcomes Platinum Resistance in Basal-Like Breast Cancer

Checkpoint Kinase 1 Pharmacological Inhibition Synergizes with DNA-Damaging Agents and Overcomes Platinum Resistance in Basal-Like Breast Cancer

CDKN1A upregulation and cisplatin‑pemetrexed resistance in non‑small cell lung cancer cells

DNA damage checkpoint kinases in cancer

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