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

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.

Natural Products, Alone or in Combination with FDA-Approved Drugs, to Treat COVID-19 and Lung Cancer

“…As regards lung cancer, significant progress has been made in the research of natural product-based nanomedicines [ 163 , 164 ] and combination drug therapies [ 165 , 166 ], which can provide some reference for the related drug discovery and development for COVID-19. In this section, we mainly focused on the nanodrug strategy (containing natural products and FDA-approved drugs) to reveal its unique advantage in the research and development of anti-lung cancer drugs.…”

Overview of Evidence-Based Chemotherapy for Oral Cancer: Focus on Drug Resistance Related to the Epithelial-Mesenchymal Transition

“…Cisplatin is one of the most commonly used platinum-based chemotherapeutic agents and has shown efficacy in the treatment of various types of cancer, including breast cancer [ 76 ], lung cancer [ 77 ], and HNC [ 78 , 79 ]. The mode of utilization of cisplatin has undergone changes a number of times since it was first discovered in 1978 [ 80 , 81 ].…”

Cell Line Models for Acquired Resistance to First-Line Osimertinib in Lung Cancers—Applications and Limitations

“…Our search criteria included the following terms: “osimertinib,” “resistance,” “lung cancer,” and “cell line” or “cell lines.” We also manually scanned the reference lists of selected articles for additional eligible publications. We finally identified 29 relevant papers [ 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 ]. We excluded 2 of these papers [ 47 , 49 ], as they used osimertinib-resistant cell lines that had been established in other studies included in our survey.…”

“…The authors showed that MEK inhibitors (GSK1120212 or PD-0325901) combined with osimertinib reduced MCL-1 expression and could overcome the resistance [ 34 ]. The same group reported in a later study that honokiol (a natural product isolated from the bark, seed cones, and leaves of trees belonging to the genus Magnolia ) plus osimertinib enhanced MCL-1 reduction by suppressing ERK-dependent MCL-1 phosphorylation [ 47 ], and that the histone deacetylase inhibitor (LBH589) enhanced the effects of osimertinib in the resistant cells by decreasing levels of p-ERK and increasing BIM levels [ 49 ]. Another group reported that in experiments using PC9 and H1975 cells, BIM downregulation was the mechanism of AR to osimertinib.…”

“…We finally identified 29 relevant papers . We excluded 2 of these papers [47,49], as they used osimertinib-resistant cell lines that had been established in other studies included in our survey.…”