Drug Combination Appears to Boost Breast Cancer Drug's Effectiveness
A recent study found that combining a well-known breast cancer drug with a lung cancer drug, at least in cells in the laboratory, was significantly more effective in killing cancer cells.
The breast cancer drug was palbociclib, marketed by Pfizer as Ibrance, and the lung cancer drug was Pfizer’s Xalkori (crizotinib). Researchers at The Institute of Cancer Research (ICER), London, and UCL Cancer Institute, found that palbociclib resistance is driven by a protein that is targeted by crizotinib. That provides a mechanistic rationale for using the drugs together and would also open up additional indications for the drug combination.
Palbociclib is one of several drugs used to treat hormone receptor-positive breast cancer. It acts by blocking two proteins, CDK4 and CDK6, which promote cancer cell division and progression. But cancers may develop resistance to palbociclib by activating a molecule called CDK2, which can stimulate cell division without CDK4/6.
The researchers discovered that CDK2 can, when CDK 4/6 is suppressed or absent, signals cell division by way of a cellular control pathway that involves the MET and FAK molecules. As a result, they found that using CDK4/6 inhibitors like palbociclib with crizotinib resulted in a combination treatment more effective than either drug on its own.
The combination not only blocks cancer cell division, but induces sensescence, where the cancer cells sort of go to sleep, rather than die.
At this point, the combination has been tested in cells in the laboratory, but since both drugs are approved, it shouldn’t be a great leap to run a clinical trial of the combination.
“Cancer’s ability to adapt, evolve and become drug resistant is the biggest challenge we face in creating more effective treatments for this disease,” stated Paul Workman, study co-leader and chief executive officer of The Institute of Cancer Research, London. “In this study, we sought to understand exactly how resistance occurs to an important family of breast cancer drugs, so that we can stay one step ahead of the cancer. We have shown the potential of combining two precision medicines for breast and lung cancer together to create a two-pronged attack that strips cancer cells of their resistance.”
The research was published in the journal Oncogene.
“Our evidence shows that existing medicines could be used to overcome resistance to treatment in a frequent form of breast cancer in women,” stated Sibylle Mittnacht, study co-lead and professor of Molecular Cancer Biology at UCL Cancer Institute. “In addition, use of a current breast cancer medicine together with these other medicines could be a new, promising route for the treatment of lung and several other cancers.”
In the study, the authors note that other CDK4/6 targeting inhibitors include abemaciclib (Eli Lilly’s Verzenio) and ribociclib (Novartis’ Kisqali), have been approved in combination with hormone therapy in breast cancer. “However, evidence for clinical benefit has not been extended to other cancer types thus far, and relapse under therapy is frequent in the approved indication in breast cancer.”
Palbociclib has typically been described as one of the biggest advances in breast cancer treatment in the last 20 years. The possibility of making it even more effective with a double-combination treatment is good news for patients and undoubtedly of significant interest to the companies manufacturing the drugs.