Overcoming acquired resistance of EGFR-mutant NSCLC cells to the third generation EGFR inhibitor, osimertinib, with the natural product honokiol.
Hongjing ZangGuoqing QianJack ArbiserTaofeek K OwonikokoSuresh S RamalingamSongqing FanShi-Yong SunPublished in: Molecular oncology (2020)
The development of acquired resistance to osimertinib (Osim) (AZD9291 or TAGRISSOTM ), an FDA-approved third-generation epidermal growth factor receptor (EGFR) inhibitor for the treatment of EGFR-mutant nonsmall cell lung cancer (NSCLC), limits the long-term benefits for patients. Thus, effective treatment options are urgently needed. To this end, we explored whether honokiol (HNK), a natural product with potential antitumor activity, may be used to overcome Osim resistance. The combination of HNK and Osim synergistically decreased the survival of several Osim -resistant cell lines with enhanced effects on inhibiting cell colony formation and growth and on inducing apoptosis. This combination also showed greater growth suppression of Osim-resistant xenograft tumors including those with 19del, T790M, and C797S triple mutations in nude mice. Mechanistically, the augmented induction of apoptosis by the combination is largely due to enhanced Mcl-1 reduction through facilitating its degradation. A synthetic HNK derivative exerted similar effects with greater efficacy. Our findings warrant further study of HNK and its derivatives in overcoming Osim resistance in the clinic.
Keyphrases
- epidermal growth factor receptor
- advanced non small cell lung cancer
- small cell lung cancer
- tyrosine kinase
- cell cycle arrest
- cell death
- end stage renal disease
- oxidative stress
- single cell
- endoplasmic reticulum stress
- cell therapy
- chronic kidney disease
- ejection fraction
- newly diagnosed
- primary care
- brain metastases
- type diabetes
- prognostic factors
- mesenchymal stem cells
- risk assessment
- pi k akt
- skeletal muscle
- adipose tissue
- stem cells
- insulin resistance
- combination therapy
- replacement therapy
- smoking cessation