Several cancers, including glioma and acute myeloid leukemia, carry mutations in IDH1 or IDH2. Researchers have found that these mutations impair homologous recombination, making the tumors sensitive to PARP inhibition. They showed that one such inhibitor, olaparib, killed IDH1/2-mutant cancer cells in culture and slowed tumor growth in mice.
Drugs that target mutant isocitrate dehydrogenase (IDH) genes are already in clinical trials, but a new study suggests that these mutations may have a positive side: They make tumors susceptible to PARP inhibition.
Mutations in IDH1 and IDH2 are common in low-grade gliomas and occur in several other tumor types, including acute myeloid leukemia and cholangiocarcinoma. Both isoforms normally convert isocitrate to α-ketoglutarate, but if mutated, they transform α-ketoglutarate into 2-hydroxyglutarate (2HG), which may promote tumor progression. Thus, researchers have focused on developing small-molecule inhibitors of mutant IDH1/2 to block 2HG production.
The current study, led by researchers at Yale University School of Medicine in New Haven, CT, suggests an alternative strategy that exploits an unexpected vulnerability induced by these mutations. Ranjit Bindra, MD, PhD, Peter Glazer, MD, PhD, and colleagues evaluated a panel of cancer cell lines they had engineered to carry mutations in IDH1 or IDH2. They found that one of the two major mechanisms for repairing DNA double-strand breaks, homologous recombination (HR), was faulty in the mutant cells, whereas the other mechanism, nonhomologous end-joining, functioned normally.
“They effectively demonstrated that IDH mutations produce a homologous recombination defect in model systems,” says Will Parsons, MD, PhD, of the Baylor College of Medicine in Houston, TX, who wasn't connected to this work.
HR is also faulty in tumors carrying BRCA1 or BRCA2 mutations, which are vulnerable to PARP inhibitors like olaparib (Lynparza; AstraZeneca). The team ran several experiments to determine whether these drugs would also be effective in IDH-mutant tumors. They found that olaparib and other PARP inhibitors killed cells in multiple cancer cell lines that harbor IDH1 and IDH2 mutations. In addition, glioma cell lines generated from patient tumors with IDH1 mutations were vulnerable to the investigational PARP inhibitor talazoparib (BMN-673; Medivation). In mice, olaparib slowed the growth of implanted IDH1-mutant tumors.
The findings suggest that PARP inhibitors, which are approved for certain breast and ovarian cancers, could work against a broader range of malignancies. “Any tumor with IDH mutations will likely be susceptible” to the drugs, says Bindra. “They are tissue-agnostic.”
PARP inhibitors could be effective even in the absence of IDH1/2 mutations, Bindra notes. That's because when some tumors are hypoxic, they produce 2HG. Through several laboratory assays, the researchers determined that 2HG disabled HR in cancer cells with nonmutated IDH1/2, which in turn made the cells vulnerable to PARP inhibition.
Craig Horbinski, MD, PhD, of the Northwestern University Feinberg School of Medicine in Chicago, IL, who wasn't connected to the study, praises it for “specifically identifying a connection between altered tumor metabolism and impaired DNA damage repair.”
To Howard Colman, MD, PhD, of the University of Utah Huntsman Cancer Institute in Salt Lake City, this study is important because “it opens up a very realistic and feasible treatment hypothesis to test in clinical trials.”
Bindra, Glazer, and colleagues plan to put that hypothesis to the test later this year by launching a clinical trial of olaparib and platinum-based chemotherapy in patients with glioma, cholangiocarcinoma, and other IDH-mutant cancers. –Mitch Leslie
- ©2017 American Association for Cancer Research.