Abemaciclib is an inhibitor of cyclin-dependent kinases (CDK) 4 and 6 that inhibits the transition from the G1 to the S phase of the cell cycle by blocking downstream CDK4/6-mediated phosphorylation of Rb. The effects of abemaciclib alone or combined with the third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) osimertinib were examined in a panel of PC9 and HCC827 osimertinib-resistant non-small cell lung cancer (NSCLC) cell lines carrying EGFR-dependent or-independent mechanisms of intrinsic or acquired resistance. Differently from sensitive cells, all the resistant cell lines analyzed maintained p-Rb, which may be considered as a biomarker of osimertinib resistance and a potential target for therapeutic intervention. In these models, abemaciclib inhibited cell growth, spheroid formation, colony formation, and induced senes-cence, and its efficacy was not enhanced in the presence of osimertinib. Interestingly, in osimertinib sensitive PC9, PC9T790M, and H1975 cells the combination of abemaciclib with osimertinib significantly inhibited the onset of resistance in long-term experiments. Our findings provide a preclinical support for using abemaciclib to treat resistance in EGFR mutated NSCLC patients progressed to osimertinib either as single treatment or combined with osimertinib, and suggest the combination of osimertinib with abemaciclib as a potential approach to prevent or delay osimertinib resistance in first-line treatment.

Efficacy of the cdk4/6 dual inhibitor abemaciclib in egfr-mutated nsclc cell lines with different resistance mechanisms to osimertinib / LA Monica, S.; Fumarola, C.; Cretella, D.; Bonelli, M.; Minari, R.; Cavazzoni, A.; Digiacomo, G.; Galetti, M.; Volta, F.; Mancini, M.; Petronini, P. G.; Tiseo, M.; Alfieri, R.. - In: CANCERS. - ISSN 2072-6694. - 13:1(2021), pp. 1-15. [10.3390/cancers13010006]

Efficacy of the cdk4/6 dual inhibitor abemaciclib in egfr-mutated nsclc cell lines with different resistance mechanisms to osimertinib

LA Monica S.;Fumarola C.;Cretella D.;Bonelli M.;Minari R.;Cavazzoni A.;Digiacomo G.;Galetti M.;Volta F.;Petronini P. G.;Tiseo M.
;
Alfieri R.
2021-01-01

Abstract

Abemaciclib is an inhibitor of cyclin-dependent kinases (CDK) 4 and 6 that inhibits the transition from the G1 to the S phase of the cell cycle by blocking downstream CDK4/6-mediated phosphorylation of Rb. The effects of abemaciclib alone or combined with the third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) osimertinib were examined in a panel of PC9 and HCC827 osimertinib-resistant non-small cell lung cancer (NSCLC) cell lines carrying EGFR-dependent or-independent mechanisms of intrinsic or acquired resistance. Differently from sensitive cells, all the resistant cell lines analyzed maintained p-Rb, which may be considered as a biomarker of osimertinib resistance and a potential target for therapeutic intervention. In these models, abemaciclib inhibited cell growth, spheroid formation, colony formation, and induced senes-cence, and its efficacy was not enhanced in the presence of osimertinib. Interestingly, in osimertinib sensitive PC9, PC9T790M, and H1975 cells the combination of abemaciclib with osimertinib significantly inhibited the onset of resistance in long-term experiments. Our findings provide a preclinical support for using abemaciclib to treat resistance in EGFR mutated NSCLC patients progressed to osimertinib either as single treatment or combined with osimertinib, and suggest the combination of osimertinib with abemaciclib as a potential approach to prevent or delay osimertinib resistance in first-line treatment.
2021
Efficacy of the cdk4/6 dual inhibitor abemaciclib in egfr-mutated nsclc cell lines with different resistance mechanisms to osimertinib / LA Monica, S.; Fumarola, C.; Cretella, D.; Bonelli, M.; Minari, R.; Cavazzoni, A.; Digiacomo, G.; Galetti, M.; Volta, F.; Mancini, M.; Petronini, P. G.; Tiseo, M.; Alfieri, R.. - In: CANCERS. - ISSN 2072-6694. - 13:1(2021), pp. 1-15. [10.3390/cancers13010006]
File in questo prodotto:
File Dimensione Formato  
Cancers-13-00006 2021.pdf

accesso aperto

Tipologia: Versione (PDF) editoriale
Licenza: Creative commons
Dimensione 3.13 MB
Formato Adobe PDF
3.13 MB Adobe PDF Visualizza/Apri

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11381/2886384
Citazioni
  • ???jsp.display-item.citation.pmc??? ND
  • Scopus 24
  • ???jsp.display-item.citation.isi??? 23
social impact