Combined Blockade of ATR and PARP Effective Against Glioblastoma in Mice

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The U.S. Food and Drug Administration has approved four poly(ADP-ribose) polymerase inhibitors (PARPi) for cancer treatment, but responses are not universal, even in cancers carrying BRCA1/2 mutations. On the other hand, patients whose cancer lacks deficiencies in homologous recombination sometimes benefit from regimens that combine a PARPi and a DNA-damaging agent.

Glioblastoma tumors, for example, lack driver mutations/deletions in BRCA1/2. They are homologous recombination-proficient and sometimes respond to a combination of a PARPi with temozolomide, radiation or an oncolytic virus. However, the mechanisms that govern response and nonresponse to PARPi aren't well understood, either in glioblastoma or other cancers.

Samuel D. Rabkin, PhD, virologist in the Brain Tumor Research Center, Department of Neurosurgery, Hiroaki Wakimoto, MD, PhD, associate professor of Neurosurgery at Massachusetts General Hospital, and colleagues have made a breakthrough finding of PARPi responsiveness in glioblastoma. In a paper in Nature Communications that has important implications for drug development, they report that the cyclin-dependent kinase 18 (CDK18)–ATR signaling axis regulates homologous recombination and sensitivity to PARPi.

In Vitro Findings

The researchers first screened patient-derived glioblastoma stem-like cells, which contribute to disease progression and recurrence and thus are important therapeutic targets. They determined that PARPi sensitivity was associated with amplification of MYC and MYCN, key oncogenes that contribute to cancer cell proliferation, metabolism and other tumorigenic processes.

Other key findings were that:

• MYC and MYCN transcription factors (together hereafter Myc) repressed expression of CDK18, thereby facilitating PARPi sensitivity. CDK18 has not been well characterized, but CDKs are known to play vital roles in cell cycle regulation and DNA damage responses
• Conversely, CDK18 promoted activation of ATR and homologous recombination in glioblastoma stem-like cells, ultimately making the cells refractory to PARPi. Thus, CDK18 appears to be a useful therapeutic target
• ATR inhibitors sensitized both Myc-amplified and non-Myc-amplified glioblastoma stem-like cells to PARPi

In Vivo Findings

The researchers implanted glioblastoma stem-like cells into mouse brains, then systemically administered VE822 or AZ20, which are ATR inhibitors. Both drugs crossed the blood–brain/tumor barrier and inhibited phosphorylation of Chk1 in the tumor, indicating successful ATR inhibition.

Next, the researchers evaluated the effects of a PARPi and an ATR inhibitor. They found:

• In Myc-amplified xenografts, olaparib or VE822 alone modestly but significantly extended survival compared with vehicle, and olaparib + VE822 further prolonged survival over vehicle by >60%
• In non–Myc-amplified xenografts, olaparib alone had no effect, but VE822 modestly prolonged survival, and olaparib + VE822 further extended survival

In general, the treatments were well tolerated, causing no significant changes in body weight.

Foundations for Future Research

• Myc expression/CDK18 repression is an additional pathway for "BRCAness" that offers an avenue for PARPi therapy, and CDK18 is a potentially important target for drug development
• Combined blockade of ATR and PARP may be effective in other BRCA1/2 wild-type or homologous recombination–proficient cancers
• Myc and CDK18 may prove to be predictive biomarkers of PARPi responsiveness
• Clinical studies should examine whether Myc-amplified glioblastoma and possibly other Myc-amplified brain tumors (e.g., medulloblastoma) are sensitive to PARPi alone
• The combination of an ATR inhibitor and PARPi should be evaluated in glioblastoma patients in the absence of radiation and/or temozolomide, such as in recurrent glioblastoma for which there are no current therapies

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