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  • Title: Overcoming acquired resistance of EGFR-mutant NSCLC cells to the third generation EGFR inhibitor, osimertinib, with the natural product honokiol.
    Author: Zang H, Qian G, Arbiser J, Owonikoko TK, Ramalingam SS, Fan S, Sun SY.
    Journal: Mol Oncol; 2020 Apr; 14(4):882-895. PubMed ID: 32003107.
    Abstract:
    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.
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