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Background/aim: The therapeutic strategy for patients with non-small-cell lung cancer (NSCLC) harboring the BRAF non-V600E mutation has not been established. LY3009120, a newly discovered pan-RAF inhibitor, has shown strong antitumor effects in cancers with various BRAF genotypes. This study investigated the antitumor effects of LY3009120 in NSCLC cells harboring the BRAF non-V600E mutation., Materials and Methods: We examined the antitumor effects of LY3009120 by MTS assay and flow cytometry. We analyzed the expression status of proteins by western blot. The mouse xenograft models were used for the in vivo experiments., Results: LY3009120 suppressed BRAF-related downstream pathway molecules and induced cleavage of poly ADP-ribose polymerase in all examined NSCLC cell lines. LY3009120 also inhibited in vivo tumor growth in NSCLC cells harboring the BRAF non-V600E mutation., Conclusion: LY3009120 is a potent therapeutic agent for patients with BRAF non-V600E mutant NSCLC., (Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background: The 90-kDa heat-shock protein (HSP90) is a chaperone protein expressed at high levels in cancer cells and is involved in the folding or stabilization of several client proteins, including epidermal growth factor receptor (EGFR). Ganetespib is a second-generation HSP90 inhibitor with a potent antitumor effect against various cancer types., Materials and Methods: This study examined the antitumor effect of ganetespib in EGFR-mutant non-small cell lung cancer (NSCLC) cells and experimentally established EGFR-tyrosine kinase inhibitor (TKI)-resistant cells harboring various resistance mechanisms, including EGFR T790M mutation, met proto-oncogene amplification, and epithelial-mesenchymal transition., Results: Ganetespib showed a potent antitumor effect at low concentrations, suppressing EGFR-related downstream pathway molecules and inducing cleavage of poly ADP-ribose polymerase in all examined EGFR-TKI-resistant cell lines in vitro. Ganetespib also inhibited in vivo tumor growth in resistant cells harboring EGFR T790M., Conclusion: Ganetespib might be a promising therapeutic option for the treatment of patients with EGFR-TKI-resistant NSCLC., (Copyright© 2019, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background: In lung cancer, epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor sensitizing mutations co-existing with rare minor EGFR mutations are known as compound mutations. These minor EGFR mutations can lead to acquired resistance after EGFR tyrosine kinase inhibitor treatment, so determining the mutation status of patients is important. However, using amplicon-based targeted deep sequencing based on next-generation sequencing to characterize mutations is prone to sequencing error. We therefore assessed the benefit of incorporating molecular barcoding with high-throughput sequencing to investigate genomic heterogeneity in treatment-naïve patients who have undergone resection of their non-small cell lung cancer (NSCLC) EGFR mutations., Methods: We performed amplicon-based targeted sequencing with the molecular barcoding system (MBS) to detect major common EGFR mutations and uncommon minor mutations at a 0.5% allele frequency in fresh-frozen lung cancer samples., Results: Profiles of the common mutations of EGFR identified by MBS corresponded with the results of clinical testing in 63 (98.4%) out of 64 cases. Uncommon mutations of EGFR were detected in seven cases (10.9%). Among the three types of major EGFR mutations, patients with the G719X mutation had a significantly higher incidence of compound mutations than those with the L858R mutation or exon 19 deletion (p = 0.0052). This was validated in an independent cohort from the Cancer Genome Atlas dataset (p = 0.018)., Conclusions: Our findings demonstrate the feasibility of using the MBS to establish an accurate NSCLC patient genotype. This work will help understand the molecular basis of EGFR compound mutations in NSCLC, and could aid the development of new treatment modalities.