Specific HER2 Exon 20 Gly776 Deletion-Insertions in Non-Small Cell Lung Cancer: Structural Analysis and Sensitivity to HER2-Targeted Tyrosine Kinase Inhibitors.

Background: HER2 exon 20 insertions remain a subset heterogeneous alterations in lung cancer, with currently unmet need for precision targeted therapy. G776delinsVC, a typical HER2 exon 20 deletion-insertion at codon Gly776, was reported to respond discrepantly to afatinib compared with the predominant insertion A775_G776insYVMA (YVMA). However, it lacks structural evidence to illustrate the possible mechanism and predict the binding activities of its similar variants over YVMA insertion to HER2-targered tyrosine kinase inhibitors (TKIs). Methods: Real-world cohort study was performed to investigate clinical outcomes with HER2-targeted TKI afatinib and pyrotinib, and structural analysis for exon 20 Gly776 deletion-insertions G776delinsVC, G776delinsLC and G776delinsVV, and YVMA by molecular dynamics simulation and cellular kinase inhibition assay were provided for full exploration. Results: Afatinib revealed low objective response rate (ORR) of 0-9.5% and short median progression-free survival (mPFS) of 2.8-3.2 months for YVMA, but with higher ORR of 20-28.6% and longer mPFS of 4.3-7.1 months for G776delinsVC. Pyrotinib presented significantly improved PFS benefit than afatinib for G776delinsVC and YVMA as first-line (median, 6.8 vs. 3.4 months, p = 0.010) or second-line therapy (median, 5.8 vs. 2.8 months, p < 0.001). No significant difference was observed on drug binding pocket and TKI binding activity between G776delinsVC, G776delinsLC and G776delinsVV, and both afatinib and pyrotinib showed favorable binding activity. YVMA insertion significantly affected the loop region with altering HER2 protein secondary structure and forming steric hindrance to binding of afatinib. Pyrotinib showed the best selectivity to HER2, with more favorable activity to YVMA than afatinib indicated by cellular inhibition assay. Conclusion: Both afatinib and pyrotinib showed favorable activity for NSCLC patients with HER2 exon 20 Gly776 deletion-insertions. Pyrotinib revealed more potent activity to A775_G776insYVMA insertion than afatinib due to the steric binding hindrance induced by YVMA.

The Lifted Veil of Uncommon EGFR Mutation p.L747P in Non-Small Cell Lung Cancer: Molecular Feature and Targeting Sensitivity to Tyrosine Kinase Inhibitors.

OBJECTIVES: The uncommon p.L747P mutation in epidermal growth factor receptor (EGFR) exon 19 reveals to alter the response to tyrosine kinase inhibitors (TKIs) in patients diagnosed with advanced non-small cell lung cancer (NSCLC). However, the underlying mechanism is still not clear. This study aimed to investigate the clinical outcomes, binding affinities, and modes of action of currently available EGFR TKIs towards p.L747P mutation. MATERIALS AND METHODS: Clinical data of NSCLC patients harboring p.L747P mutation who had received different generations of EGFR TKIs were collected from medical records. Computational structure of p.L747P was constructed and in vitro cellular kinase inhibition assay and mice xenograft experiment were performed to predict and confirm the binding affinities and antitumor activities of diverse EGFR TKIs. RESULTS: A total of five metastatic NSCLC patients with p.L747P mutation were included in the final analysis. Patients treated with second-generation (2G) TKI afatinib achieved numerically longer progression-free survival (range 2.4-8.5 months) than that with first-generation (1G, range 1.4-5.5 months) or third-generation (3G, range 1.6-7.5 months) TKIs. None of the patients administered 1G or 3G TKIs achieved tumor response, but two-thirds of them treated with afatinib achieved partial response. Dynamics simulation predicted that 2G TKIs presented the best binding affinity to p.L747P mutation. The cellular kinase inhibition assay and mice xenograft experiment confirmed that afatinib could potently inhibit p.L747P-mutant cells and significantly reduce p.L747P-mutant tumor growth (P< 0.001), together with reduced phosphorylation of EGFR and its downstream signalings. CONCLUSIONS: The uncommon p.L747P mutation in EGFR exon 19 resulted in a poor response to first-generation EGFR TKIs. Afatinib revealed a better clinical response and binding affinity compared with osimertinib for this specific alteration.

PON1 L55M polymorphism might contribute to the risk of cancer.

INTRODUCTION: The results involved in correlation of PON1 L55M polymorphism and cancer risk are still inconsistent and controversial. Therefore, we performed this comprehensive meta-analysis for the effects of PON1 L55M polymorphism and cancer risk. EVIDENCE ACQUISITION: We carried out a database search in PubMed (Medline) and EMBASE covering all published articles. The strength of association between PON1 L55M polymorphism and cancer risk was estimated by pooled ORs with corresponding 95% confidence intervals (CI). EVIDENCE SYNTHESIS: Twenty-one independent case-control studies concerned with association between PON1 L55M polymorphism and cancer risk were finally included in this meta-analysis. We found that there was a statistical significance between PON1 L55M polymorphism and cancer risk (OR=1.21, 95% CI: 1.04-1.40). In stratified analyses by site of cancer, statistically significant increased breast cancer risk was found (OR=2.04, 95% CI: 1.29-3.21). In stratified analyses by ethnicity, statistically significant increased cancer risk was found in Caucasian populations (OR=1.25, 95% CI: 1.03-1.51). In stratified analyses by source of control, significant increased cancer risk was found in hospital-based studies (OR=1.26, 95% CI: 1.10-1.44). CONCLUSIONS: This meta-analysis suggested that PON1 L55M polymorphism might increase the risk of cancer.

[Clinical observation of superior gluteal nerve entrapment syndrome treated with needle-in-row combined with herb-partition moxibustion].

OBJECTIVE: To compare the effects of need-in-row combined with herb-partition moxibustion,need-in-row and conventional acupuncture for superior gluteal nerve entrapment syndrome. METHODS: Totally 105 patients were randomly assigned into a combination group,a need-in-row group and an acupuncture group,35 cases in each one. In the combination group and needle-in-row group,needle-in-row therapy was used at the pain tendon region of the pathological waist-hip part,and TDP was combined. Also,herb-partition moxibustion was applied at the same part after needle-in-row in the combined group. In the acupuncture group,conventional acupuncture was implemented at Weizhong(BL 40),Yanglingquan(GB 34),Zhibian(BL 54),Huantiao(GB 30),Sanyinjiao(SP 6) and Jiaji of L1-L5(EX-B 2),and TDP was applied. All the treatment was given once a day for four weeks. The changes of pain scores were compared after treatment. RESULTS: The pain scores decreased obviously after treatment in all the groups(all P<0.05). The scores of the combination group and the needle-in-row group declined more apparently than that of the acupuncture group(both P<0.05). The score of the combination group reduced more obviously than that of the needle-in-low group(P<0.05). The markedly effective rates of the combination group and the needle-in-row group were 88.6%(31/35) and 68.6%(24/35),which were higher than 40.0%(14/35) of the acupuncture group(both P<0.05),and the markedly effective rate of the combination group was better than that of the needle-in-row group(P<0.05). CONCLUSIONS: Need-in-row combined with herb-partition moxibustion show definite effect for superior gluteal nerve entrapment syndrome,and it is better than those of simple needle-in-row therapy and conventional acupuncture.