Palbociclib Plus Osimertinib Under Study in Tyrosine Kinase Inhibitor–Resistant NSCLC
Posted: Monday, September 21, 2020
Diansheng Zhong, MD, of the Tianjin Medical University General Hospital, China, and colleagues conducted a study to assess whether adding the CDK4/6 inhibitor palbociclib to the third‐generation EGFR tyrosine kinase inhibitor osimertinib could enhance the sensitivity of the resistant cells to osimertinib in tyrosine kinase inhibitor–resistant non–small cell lung cancer (NSCLC). The results, which were published in Thoracic Cancer, suggested that targeting CDK4/6 may prove to be effective in this patient population.
Using EGFR‐mutant NSCLC cells, the investigators established an osimertinib‐resistant cell line. Cell counting kit‐8, western blot analysis, reverse transcription–polymerase chain reaction, and flow cytometry were performed to examine whether an abnormal cell cycle may be associated with acquired osimertinib resistance. They also sought to determine whether single-agent palbociclib or its combination with osimertinib could overcome this resistance.
Based on the results of the cell counting kit-8 assay, the resistant cell line seemed to exhibit increased sensitivity to palbociclib compared with the sensitive cell line. Furthermore, in terms of the cell cycle, the resistant cell line had fewer G1 phase cells than the sensitive cell line (30.9% vs. 44.8%, respectively). Western blot analysis revealed the upregulation of CDK4, E2F1, and hyperphosphorylation of retinoblastoma tumor suppressor protein in the resistant cell line. After treatment with palbociclib, the resistant cell line exhibited a significant increase in the proportion of G1 phase cells. Combined treatment with palbociclib and osimertinib appeared to decrease the survival of the resistant cell line by cell-cycle arrest.
“The combination of CDK4/6 inhibitor palbociclib and osimertinib downregulated the phosphorylation of retinoblastoma tumor suppressor protein, blocked the acquired resistant cells in G1 phase, and controlled cell proliferation,” the investigators stated. “Our study sheds new light onto the mechanisms of osimertinib resistance and provides a rationale for targeting CDK4/6….”
Disclosure: The study authors reported no conflicts of interest.