Novel agent restores breast tumors' vulnerability to promising class of drugs, study finds
For cancers that resist arrest by a muscular new class of drug agents, the addition of a structurally distinct, protein-targeting drug can put the disease in – or back in – check, a new study led by scientists Dana-Farber Cancer Institute scientists indicates.
The novel drug, named dinaciclib, works hand-in-hand with agents known as PARP inhibitors to hinder cancer cells from repairing certain types of damage to their DNA. Without such repairs, the cells can become so genomically dysfunctional that they have little recourse but to die.
The research, reported online today by Cell Reports, was conducted in laboratory samples of triple-negative breast cancer and in mice carrying tumor tissue from human patients. When investigators treated the samples and the animals with a PARP inhibitor and dinaciclib, tumors that previously hadn’t responded to PARP inhibitors stopped growing, as did tumors that initially did respond to the drugs but had become resistant to them. (Triple-negative breast cancer doesn’t grow in response to the hormones estrogen and progesterone, doesn’t harbor unduly high levels of the protein HER2, has not been amenable to targeted therapies, and remains the most challenging breast cancer subset.)
“The findings suggest that dinaciclib and similar agents can restore the effectiveness of PARP inhibitors in tumors that have become resistant to such inhibitors – and even create a vulnerability to PARP inhibitors in tumors that initially didn’t respond to them,” says study senior author Geoffrey Shapiro, MD, PhD, of Dana-Farber, who led the study with first author Shawn Johnson of his lab. “Although this study was conducted in triple-negative breast cancer, it may have applicability to a wide array of other cancers as well.”
Since their development in the mid-2000s, PARP [or poly (ADP-ribose) polymerase] inhibitors have become one of the most promising forms of targeted cancer therapies. Because they work by jamming a critical DNA-repair mechanism, they’ve been studied primarily in cancers – such as breast and ovarian tumors with BRCA gene mutations – with a breakdown in another DNA-repair pathway. The double hit of a malfunctioning repair mechanism and a chemically blocked second mechanism can lead to a cancer cell’s undoing. In 2014, the PARP inhibitor olaparib was approved by the U.S. Food and Drug Administration (FDA) for advanced ovarian cancers that are deficient in DNA repair.
The limitations of PARP inhibitors are two-fold: They are effective only in cancers that already are poor at DNA repair; and their effectiveness tends to diminish over time, as cancer cells find alternate routes for fixing DNA damage. This has prompted scientists to look for compounds capable of disrupting DNA repair, potentially by interfering with cell proteins that play a role in the process. Such drugs could potentially turn PARP inhibitor-resistant cancers into inhibitor-sensitive ones.
To identify such a drug, researchers tested dozens of compounds to see if any inhibited a protein known as CDK12 (or cyclin-dependent kinase 12), which regulates a broad range of genes involved in DNA repair. Most CDK inhibitors, either FDA-approved or in clinical testing, could not inhibit CDK12. However, one of the compounds with unique structural characteristics – dinaciclib – did.
Researchers then administered the drug in BRCA-mutated triple-negative breast cancer tumors that were resistant to a PARP inhibitor. In both laboratory tissue samples and in mice, dinaciclib hobbled the cancer’s makeshift DNA-repair system and restored the tumors’ vulnerability to the PARP inhibitor. This occurred in tumors that were PARP inhibitor-resistant from the start as well as those that initially responded to PARP inhibitors but became resistant later on. In tumors that were sensitive to PARP inhibitors, the addition of dinaciclib had an especially dramatic effect: tumors whose growth had merely been stymied by the PARP inhibitor now began to durably shrink.
The drug combination produced few side effects in mice, the authors report. Because dinaciclib targets cyclin-dependent kinases other than CDK12, it may reduce the negative impact of the drug on normal cells in the body, Johnson remarked.
Shapiro and his colleagues are currently leading a clinical trial of PARP inhibitors in patients with a wide array of solid tumors, primarily breast and ovarian cancers. Based on the results of the new study, the trial will branch into separate arms in which the PARP inhibitor/dinaciclib combination is tested in three groups of breast or ovarian cancer patients: those whose tumors don’t have BRCA mutations; those with BRCA-positive tumors that have not previously been treated with a PARP inhibitor; and those with BRCA mutations that have become resistant to a PARP inhibitor.
The research work was supported by the National Institutes of Health (grant numbers RO1 CA090687 and RO1 Diversity Supplement); a Dana-Farber Specialized Program of Research Excellence (SPORE) Breast Cancer grant (P50 CA089383); a SPORE Diversity Career Development Award; a Susan G. Komen Investigator Initiated Research grant (IIR2223953); a Dana-Farber Claudia Adams Barr Award; a National Health and Medical Research Council of Australia Fellowship; an Instituto de Salud Carlos III grant (PI12/02606); the Asociacion Espanola Contra el Cancer; and a Deutsche Forschungsgemeinschaft grant (GE 976/9-1).