Overcoming acquired resistance of EGFR‐mutant NSCLC cells to the third generation EGFR inhibitor, osimertinib, with the natural product honokiol

The development of acquired resistance to osimertinib (Osim) (AZD9291 or TAGRISSO(TM)), 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.