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CDK4/6 inhibitor palbociclib overcomes acquired resistance to third‐generation EGFR inhibitor osimertinib in non‐small cell lung cancer (NSCLC)
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CDK4/6 inhibitor palbociclib overcomes acquired resistance to third‐generation EGFR inhibitor osimertinib in non‐small cell lung cancer (NSCLC)
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CDK4/6 inhibitor palbociclib overcomes acquired resistance to third‐generation EGFR inhibitor osimertinib in non‐small cell lung cancer (NSCLC)
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Journal Article
CDK4/6 inhibitor palbociclib overcomes acquired resistance to third‐generation EGFR inhibitor osimertinib in non‐small cell lung cancer (NSCLC)
2020
Overview
Background The third‐generation EGFR‐TKI, represented by osimertinib, has been widely used in clinical practice; however, resistance eventually emerges. At present, it remains unclear whether an abnormal cell cycle is involved in acquired resistance, and whether the combination of palbociclib (CDK4/6 inhibitor) and osimertinib can overcome the third‐generation TKI resistance. Methods We established osimertinib‐resistant cells (H1975 OR) derived from EGFR‐mutant NSCLC cells H1975. Drug effects on cells were assessed with Cell Counting Kit‐8 (CCK8). Protein alterations were detected with western blot analysis. RT‐PCR was used to evaluate the differences of gene mRNA. Cell cycle distribution of H1975 S and H1975 OR cells was compared using flow cytometry. Results Compared with H1975, the sensitivity of H1975OR to the CDK4/6 inhibitor was increased and the proportion of cells in G1 phase was decreased. The mRNA level of CDK4, CDK 6 and the protein level of CDK4, pRB were increased in H1975OR. In the H1975OR cells, palbociclib significantly increased the proportion of G1 phase cells. The combination of osimertinib and palbociclib synergistically decreased the survival of H1975OR by cell cycle arrest. Combined treatment was found to inhibit the initial phosphorylation of RB by inhibiting the function of CDK4/6, significantly reducing the level of p‐RB, and blocking cell proliferation. Conclusions An osimertinib acquired resistance cell line (H1975 OR) was successfully established. The expression of cell cycle related genes was altered in H1975OR. The expression of CDK4 and the phosphorylation of Rb, the downstream molecule of CDK4/6, was increased in H1975OR cells. The combination of CDK4/6 inhibitor palbociclib and osimertinib could overcome the acquired resistance of osimertinib.
Publisher
John Wiley & Sons Australia, Ltd,John Wiley & Sons, Inc,Wiley
Subject
/ Acrylamides - therapeutic use
/ Aniline Compounds - pharmacology
/ Aniline Compounds - therapeutic use
/ Antineoplastic Combined Chemotherapy Protocols - pharmacology
/ Antineoplastic Combined Chemotherapy Protocols - therapeutic use
/ Carcinoma, Non-Small-Cell Lung - drug therapy
/ Carcinoma, Non-Small-Cell Lung - pathology
/ CDK4/6 inhibitor palbociclib
/ Female
/ Humans
/ Kinases
/ Lung Neoplasms - drug therapy
/ Male
/ Mutation
/ Original
/ Piperazines - therapeutic use
/ Software
/ third‐generation epidermal growth factor receptor (EGFR) tyrosine‐kinase inhibitor (TKI)
