Palbociclib and Crizotinib More Effective When Paired Together

When palbociclib, a breast cancer drug, and crizotinib, a lung cancer drug, were used in combination, they were more effective together against cancer cells than they were used separately, according to new research published in Oncogene. The researchers said that the findings suggest the combination approach could mean using palbociclib in other tumor types.

Palbociclib treats patients with hormone receptor-positive breast cancer by blocking cyclin-dependent kinases (CDK) 4 and 6. However, cancers become resistant to the treatment by activating CDK2.

"Cancer's ability to adapt, evolve and become drug resistant is the biggest challenge we face in creating more effective treatments for the disease,” study colead author Paul Workman, FMedSci, FRS, chief executive of The Institute of Cancer Research, London, said in a statement. “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.”

CDK2 compensates for CDK4/6 inhibition because of signaling through a pathway involving the MET and FAK molecules. The researchers paired palbociclib with crizotinib because the lung cancer treatment blocks MET activity. They found that inhibiting both MET/FAK and CDK4/6 curbs cancer cells’ ability to proliferate.

After testing on cancer cells from different organs in a laboratory, the researchers suggested that there is potential to expand the use of CDK4/6 inhibitors, like palbociclib, to patients beyond those who have breast 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,” Workman said. “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."

The researchers also identified FAK as a key downstream component that could potentially be a better target than MET because it can be activated through MET-independent signaling routes. There are a number of ongoing trials studying the inhibition of FAK in various cancers, which could lead to testing this idea.

“Our results suggest an opportunity for use of FAK inhibitors in conjunction with CDK4/6 [inhibitors] as a potentially powerful approach to improve the outcome for patients treated with CDK4/6-targeted therapies or to expand the current, approved indications through mechanism-based targeted combinations,” the authors concluded.

Reference

Zhang C, Stockwell SR, Elbanna M, et al. Signalling involving MET and FAK supports cell division independent of the activity of the cell cycle-regulating CDK4/6 kinases. Oncogene. 2019;38(30):5905-5920. doi: 10.1038/s41388-019-0850-2.