Next-Generation CDK2/9 Inhibitors and Anaphase Catastrophe in Lung Cancer

Kawakami, Masanori; Mustachio, Lisa Maria; Rodriguez‐Canales, Jaime; Mino, Barbara; Roszik, Jason; Tong, Pan; Wang, Jing; Lee, John; Myung, Ja Hye; Heymach, John V.; Johnson, Faye M.; Hong, Seungpyo; Zheng, Lin; Hu, Shanhu; Villalobos, Pamela; Behrens, Carmen; Wistuba, Ignacio I.; Freemantle, Sarah J.; Liu, Xi; Dmitrovsky, Ethan

doi:10.1093/jnci/djw297

Cited by 39 publications

(62 citation statements)

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“…Anaphase catastrophe was observed by this knockdown of CDK2 and this finding independently confirmed the pharmacologic effects of CDK2 antagonists (34,44). In addition to seliciclib, anaphase catastrophe engagement was observed using other selective CDK2 or pan-CDK inhibitors, that include dinaciclib (SCH727965, Merck) (IC50 for CDK1: 3 nM, CDK2: 1 nM, CDK5: 1 nM, and CDK9: 4 nM) (43,49), CCT68127 (Cyclacel) (IC50 for CDK2 and 30 nM, CDK9: 110 nM) (44) and CYC065 (PubChem ID: 24983461, Cyclacel) (IC50 for CDK2: 5 nM and CDK9: 26 nM) (44). Notably, anaphase catastrophe induced after CDK2 inhibitor treatment was observed not only in lung cancer cells, but also in preliminary evidence from other aneuploid cancer cells (unpublished observations from Ethan Dmitrovsky laboratory).…”

Section: Anaphase Catastrophesupporting

confidence: 75%

“…Therefore, anaphase catastrophe following CDK2 antagonism is detected preferentially in cells having supernumerary centrosomes while relatively sparing normal cells with two centrosomes. Consistent with this view, it was experimentally shown that anaphase catastrophe was not substantially observed after treatment of immortalized pulmonary epithelial cells that are not chromosomally unstable as are lung cancer cells (34,44). Normal cells like hematopoietic and gastric cells are affected by conventional chemotherapy because of their proliferative properties.…”

Section: Anaphase Catastrophementioning

confidence: 66%

“…The association between anaphase catastrophe and CDK2 inhibition was first uncovered after treating lung cancers with seliciclib (CYC202, Cyclacel), an orally bioavailable and fully reversible inhibitor of CDK2 activity with less evident effects against CDK5, CDK7, and CDK9 activity (IC50 for CDK2: 100 nM, CDK5: 160 nM, CDK7: 540nM, and CDK9: 950 nM) (34,35,44–47). When aneuploid lung cancer cells were exposed to seliciclib, irreversible anti-proliferative effects were unexpectedly observed (34).…”

Section: Anaphase Catastrophementioning

confidence: 99%

“…Given this, inducing anaphase catastrophe is an attractive strategy to explore for cancer therapy (35,40–42). Interestingly, several agents that antagonize cyclin-dependent kinase 1 (CDK1) or CDK2 activities were reported to cause anaphase catastrophe in cancer cells (34,43,44). …”

Section: Introductionmentioning

confidence: 99%

“…Anaphase catastrophe confers apoptotic death of cancer cells while relatively sparing normal cells, as will be discussed. Intriguingly, this mechanism is preferentially engaged in KRAS mutant oncoprotein-expressing lung cancer (34,35,44). The mechanistic basis for this association will be discussed.…”

Section: Introductionmentioning

confidence: 99%

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Engaging Anaphase Catastrophe Mechanisms to Eradicate Aneuploid Cancers

Kawakami

Mustachio

Liu

et al. 2018

Molecular Cancer Therapeutics

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Cancer cells often have supernumerary centrosomes that promote genomic instability, a pathognomonic feature of cancer. During mitosis, cancer cells with supernumerary centrosomes undergo bipolar cell division by clustering centrosomes into two poles. When supernumerary centrosome clustering is antagonized, cancer cells are forced to undergo multipolar division leading to death of daughter cells. This proapoptotic pathway, called anaphase catastrophe, preferentially eliminates aneuploid cancer cells and malignant tumors in engineered mouse models. Anaphase catastrophe occurs through the loss or inhibition of the centrosomal protein CP110, a direct cyclin dependent kinase 1 (CDK1) and CDK2 target. Intriguingly, CP110 is repressed by the KRAS oncoprotein. This sensitizes KRAS-driven lung cancers (an unmet medical need) to respond to CDK2 inhibitors. Anaphase catastrophe-inducing agents like CDK1 and CDK2 antagonists are lethal to cancer cells with supernumerary centrosomes, but can relatively spare normal cells with two centrosomes. This mechanism is proposed to provide a therapeutic window in the cancer clinic following treatment with a CDK1 or CDK2 inhibitor. Taken together, anaphase catastrophe is a clinically-tractable mechanism that promotes death of neoplastic tumors with aneuploidy, a hallmark of cancer.

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Section: Anaphase Catastrophesupporting

confidence: 75%

Section: Anaphase Catastrophementioning

confidence: 66%

Section: Anaphase Catastrophementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Engaging Anaphase Catastrophe Mechanisms to Eradicate Aneuploid Cancers

Kawakami

Mustachio

Liu

et al. 2018

Molecular Cancer Therapeutics

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A rapid and sensitive bioanalytical LC–MS/MS method for the quantitation of a novel CDK5 inhibitor 20–223 (CP668863) in plasma: Application to in vitro metabolism and plasma protein‐binding studies

Bala

Chhonker

Crawford

et al. 2020

Biomedical Chromatography

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A rapid, selective, and sensitive liquid chromatography coupled with tandem mass spectrometry (MS/MS) method was developed and validated for the quantitation of the novel CDK5 inhibitor ‘20–223' in mouse plasma. Separation of analytes was achieved by a reverse‐phase ACE Excel C18 column (1.7 μm, 100 × 2.1 mm) with gradient elution using 0.1% formic acid (FA) in methanol and 0.1% FA as the mobile phase. Analytes were monitored by MS/MS with an electrospray ionization source in the positive multiple reaction monitoring mode. The MS/MS response was linear over the concentration range 0.2–500 ng/mL for 20–223. The within‐ and between‐batch precision were within the acceptable limits as per Food and Drug Administration guidelines. The validated method was successfully applied to plasma protein binding and in vitro metabolism studies. Compound 20–223 was highly bound to mouse plasma proteins (>98% bound). Utilizing mouse S9 fractions, in vitro intrinsic clearance (CLint) was 24.68 ± 0.99 μL/min/mg protein. A total of 12 phase I and II metabolites were identified with hydroxylation found to be the major metabolic pathway. The validate method required a low sample volume, was linear from 0.2 to 500 ng/mL, and had acceptable accuracy and precision.

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Cigarette smoke condensate induces centrosome clustering in normal lung epithelial cells

et al. 2023

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Background Unlike normal cells, cancer cells frequently have multiple centrosomes that can cluster to form bipolar mitotic spindles and allow for successful cell division. Inhibiting centrosome clustering, therefore, holds therapeutic promise to promote cancer cell‐specific cell death. Methods We used confocal microscopy, real‐time PCR, siRNA knockdown, and western blot to analyze centrosome clustering and declustering using normal lung bronchial epithelial and nonsmall‐cell lung cancer (NSCLC) cell lines. Also, we used Ingenuity Pathway Analysis software to identify novel pathways associated with centrosome clustering. Results In this study, we found that exposure to cigarette smoke condensate induces centrosome amplification and clustering in human lung epithelial cells. We observed a similar increase in centrosome amplification and clustering in unexposed NSCLC cell lines which may suggest a common underlying mechanism for lung carcinogenesis. We identified a cyclin D2‐mediated centrosome clustering pathway that involves a sonic hedgehog‐forkhead box protein M1 axis which is critical for mitosis. We also observed that cyclin D2 knockdown induced multipolar mitotic spindles that could eventually lead to cell death. Conclusions Here we report a novel role of cyclin D2 in the regulation of centrosome clustering, which could allow the identification of tumors sensitive to cyclin D2 inhibitors. Our data reveal a pathway that can be targeted to inhibit centrosome clustering by interfering with the expression of cyclin D2‐associated genes.

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Next-Generation CDK2/9 Inhibitors and Anaphase Catastrophe in Lung Cancer

Abstract: Next-generation CDK2/9 inhibition elicits marked antineoplastic effects in lung cancer via anaphase catastrophe and reduced PEA15 phosphorylation.

Cited by 39 publications

References 40 publications

Engaging Anaphase Catastrophe Mechanisms to Eradicate Aneuploid Cancers

Engaging Anaphase Catastrophe Mechanisms to Eradicate Aneuploid Cancers

A rapid and sensitive bioanalytical LC–MS/MS method for the quantitation of a novel CDK5 inhibitor 20–223 (CP668863) in plasma: Application to in vitro metabolism and plasma protein‐binding studies

Cigarette smoke condensate induces centrosome clustering in normal lung epithelial cells

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