Recently published in Oncogene¸ researchers from The Institute of Cancer Research (London, UK) and the University College London Cancer Institute (UK) have discovered that the combination of the breast cancer drug, palbociclib, combined with the lung cancer drug, crizotinib, was significantly more effective against cancer cells than either drug on its own.
Palbociclib is used to treat patients with hormone receptor-positive breast cancer by blocking the function of the two proteins CDK4 and CDK6, which promote tumor cell division and cancer progression.
Cancers can become resistant to palbociclib by activating CDK2, a molecule that drives cell division in the absence of CDK4/6. To reveal the mechanism underlying the resistance, the researchers searched systematically using robotics and sophisticated imaging to identify how CDK2 is activated to allow cells to evade CDK4/6 inhibitors. They found that CDK2 compensates for the inhibition of CDK4/6 in cancer cells by signaling via a cellular control pathway involving the molecules MET and FAK.
“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"
Study co-leader Paul Workman (The Institute of Cancer Research) commented: “Cancer’s ability to adapt, evolve and become drug resistant is the biggest challenge we face in creating more effective treatments for the disease. 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.”
Based on this, the researchers found that combining CDK4/6 inhibitor, palbociclib, together with crizotinib, a drug that blocks MET activity, created a much more effective treatment against a variety of cancer cell types grown in the lab and in human tumors growing in mice, compared with either drug on its own.
The combined drugs were found to have blocked cancer cell division and induce senescence. The researchers hope that their discoveries can be translated to patients – initially by evaluating the safety and effectiveness of combining CDK4/6 inhibitors like palbociclib with MET inhibitors such as crizotinib.
The researchers also highlight the longer-term possibility arising from their research that combining CDK4/6 inhibitors with drugs that block FAK could be even more effective and more generally applicable.
Workman concluded: “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. We still need to do more work to understand the full potential of combination treatment to increase the effectiveness of these drugs, but the approach looks highly promising and has the potential to be effective against several cancer types.”