Constitutive CHK1 Expression Drives a pSTAT3–CIP2A Circuit that Promotes Glioblastoma Cell Survival and Growth

Khanna, Anchit; Thoms, Julie A.I.; Stringer, Brett W.; Chung, Sylvia A.; Ensbey, Kathleen S.; Jue, Toni Rose; Jahan, Zeenat; Subramanian, Shruthi; Anande, Govardhan; Shen, Han; Unnikrishnan, Ashwin; McDonald, Kerrie L.; Day, Bryan W.; Pimanda, John E.

doi:10.1158/1541-7786.mcr-19-0934

Cited by 16 publications

(13 citation statements)

References 51 publications

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“…The impact of CHK1 inhibition on GB cells was also studied using SB18078 and PF477736, confirming an influence on colony and tumor sphere formation, as well as cell proliferation. Khanna et al also confirmed that CHK1 acts via protein phosphatase 2A in promoting GB cell growth [ 183 ]. Unfortunately, in AST, a phase I study on PF477736 combined with gemcitabine was terminated due to business reasons (NCT00437203) [ 29 ].…”

Section: Ddr (Radio)pharmaceuticalsmentioning

confidence: 98%

Perspective on the Use of DNA Repair Inhibitors as a Tool for Imaging and Radionuclide Therapy of Glioblastoma

Everix

Nair

Driver

et al. 2022

Cancers

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Despite numerous innovative treatment strategies, the treatment of glioblastoma (GB) remains challenging. With the current state-of-the-art therapy, most GB patients succumb after about a year. In the evolution of personalized medicine, targeted radionuclide therapy (TRT) is gaining momentum, for example, to stratify patients based on specific biomarkers. One of these biomarkers is deficiencies in DNA damage repair (DDR), which give rise to genomic instability and cancer initiation. However, these deficiencies also provide targets to specifically kill cancer cells following the synthetic lethality principle. This led to the increased interest in targeted drugs that inhibit essential DDR kinases (DDRi), of which multiple are undergoing clinical validation. In this review, the current status of DDRi for the treatment of GB is given for selected targets: ATM/ATR, CHK1/2, DNA-PK, and PARP. Furthermore, this review provides a perspective on the use of radiopharmaceuticals targeting these DDR kinases to (1) evaluate the DNA repair phenotype of GB before treatment decisions are made and (2) induce DNA damage via TRT. Finally, by applying in-house selection criteria and analyzing the structural characteristics of the DDRi, four drugs with the potential to become new therapeutic GB radiopharmaceuticals are suggested.

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Section: Ddr (Radio)pharmaceuticalsmentioning

confidence: 98%

Perspective on the Use of DNA Repair Inhibitors as a Tool for Imaging and Radionuclide Therapy of Glioblastoma

Everix

Nair

Driver

et al. 2022

Cancers

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“…Similarly, Khanna et al, in their study, showed a decrease in expression for all PP2A subunits in glioma tissues compared to healthy tissues, further strengthening the evidence of the oncogenic role of CIP2A in gliomas. Depletion of CIP2A expression in GBM cells induces senescence and prevents tumor growth in vitro and in vivo [ 60 ]. Gao et al demonstrated that knockdown of CIP2A in GBM cell lines LN229 and A172 led to an inhibition of cell activity and cell cycle arrest [ 43 ].…”

Section: Role Of Cip2a In Glioma and Gbmmentioning

confidence: 99%

The Pivotal Role of Protein Phosphatase 2A (PP2A) in Brain Tumors

Cucinotta

Filippone

Casili

et al. 2022

IJMS

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Protein phosphatase 2A (PP2A) is a highly complex heterotrimeric Ser/Thr phosphatase that regulates many cellular processes. PP2A is dysregulated in several human diseases, including oncological pathology; interestingly, PP2A appears to be essential for controlling cell growth and may be involved in cancer development. The role of PP2A as a tumor suppressor has been extensively studied and reviewed. To leverage the potential clinical utility of combination PP2A inhibition and radiotherapy treatment, it is vital that novel highly specific PP2A inhibitors be developed. In this review, the existing literature on the role of PP2A in brain tumors, especially in gliomas and glioblastoma (GBM), was analyzed. Interestingly, the review focused on the role of PP2A inhibitors, focusing on CIP2A inhibition, as CIP2A participated in tumor cell growth by stimulating cell-renewal survival, cellular proliferation, evasion of senescence and inhibition of apoptosis. This review suggested CIP2A inhibition as a promising strategy in oncology target therapy.

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“…Instead, its expression is enhanced due to constitutive DDR activity 42,51 , TP53 inactivation 20 , and EGFR pathway activation 21 , which are all molecular hallmarks of BLBC 1, 3 . Our data expand on these findings by demonstrating induction of Cip2a mRNA expression in premalignant mammary tissue of DMBA-treated mice ( Fig.…”

Section: Clinical and Functional Relevance For Cip2a In Human Blbcmentioning

confidence: 99%

CIP2A interacts with TopBP1 and is selectively essential for DNA damage-induced basal-like breast cancer tumorigenesis

Laine

Nagelli

Farrington

et al. 2020

Preprint

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Despite saturated genetic profiling of breast cancers, oncogenic drivers for the clinically challenging basal-like breast cancer (BLBC) subtype are still poorly understood. Here, we demonstrate that CIP2A is selectively essential for DNA damage-induced initiation of mouse BLBC tumors, but not of other cancer types. Mechanistically, CIP2A was discovered genome-widely the closest functional homologue for DNA-damage proteins TopBP1, RHNO, POLQ, NBN and PARP1. CIP2A directly interacts with the ATR-activation domain of TopBP1, and dampens both, chromatin binding of TopBP1 and RAD51, and G2/M checkpoint in DNA-damaged cells. CIP2A also drives BLBC-associated proliferative MYC and E2F1 signaling. Consistently with high DNA-damage response activity BLBCs, and CIP2A’s novel role in checkpoint signaling, CIP2A was found essential for DNA-damaged, and BRCA-mutant BLBC cells. Selective role for CIP2A as BLBC driver was supported by association of high CIP2A expression with poor patient prognosis only in BLBC, but not in other breast cancer types. Therapeutically, small molecule reactivators of PP2A (SMAPs) phenocopy CIP2A-dependent DNA damage response, and inhibit in vivo growth of patient-derived BLBC xenograft. In summary, we discover sub-type selective essential role for CIP2A in BLBC initiation and maintenance that can be explained by its newly discovered association with DNA-damage response, coordinated with regulation of proliferative signaling. The results also identify therapeutic strategy for CIP2A-dependent BLBCs.

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Constitutive CHK1 Expression Drives a pSTAT3–CIP2A Circuit that Promotes Glioblastoma Cell Survival and Growth

Cited by 16 publications

References 51 publications

Perspective on the Use of DNA Repair Inhibitors as a Tool for Imaging and Radionuclide Therapy of Glioblastoma

Perspective on the Use of DNA Repair Inhibitors as a Tool for Imaging and Radionuclide Therapy of Glioblastoma

The Pivotal Role of Protein Phosphatase 2A (PP2A) in Brain Tumors

CIP2A interacts with TopBP1 and is selectively essential for DNA damage-induced basal-like breast cancer tumorigenesis

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