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  • According to the literature HER mutations


    According to the literature, HER2 mutations are present in 2–4% of lung adenocarcinoma (ADC) patients. Most HER2 mutations are in-frame insertional mutations occurring at exon 20 in the protein kinase domain [[2], [3], [4], [5]]. Although several small molecules and HER2 p-Cresyl sulfate australia have been tested for treatment of these tumors, the results were generally unsatisfactory. For example, a recently published large retrospective study found that the overall response rate (ORR) for HER2-targeted TKIs, including neratinib, lapatinib and afatinib, is only 7.4% [6]. A novel pan-HER TKI, poziotinib, was recently developed for lung cancer with EGFR and HER2 exon 20 mutations. Early clinical trials for NSCLC with EGFR and HER2 exon 20 mutation are ongoing, and the ORR in the EGFR exon 20 cohort was found to equal 73% in a phase II study [7]. In addition, another novel pan-HER TKI, pyrotinib, achieved an ORR of 55% in a phase II study for HER2 mutant-pozitive advanced NSCLC [8]. The development of these de novo reagents inspired us to comprehensively evaluate the antitumor activities of poziotinib and pyrotinib for common HER2 exon 20 insertional mutations and compare them with those of eight preexisting TKIs using a mouse Ba/F3 system. Furthermore, we derived resistant clones against effective TKI through chronic exposure to the drug and searched for the resistant mechanism.
    Material and methods
    Discussion Here, we showed that among 10 relevant TKIs, poziotinib exihibited the most potent activity against three common HER2 exon 20 insertions, with the exception that GSP was confirmed to be sensitive to dacomitinib as reported previously [13,25]. The fact that poziotinib showed superior activity for H1781 harboring VC compared with afatinib was consistent with the results of a previous preclinical study [26]. To our knowledge, this study provides the first evidence showing that the HER2 C805S secondary mutation is a potential mechanism of acquired resistance against poziotinib. Because C805 forms a covalent bond with irreversible TKI, similarly to C797 of the EGFR, C805 is likely to interfere with binding to poziotinib. This result is concordant with the findings report previously by Kosaka et al. who found that YVMA with secondary C805S was resistant to neratinib or dacomitinib. [10] However, there have been no clinical reports on secondary HER2 mutations in NSCLC harboring HER2 exon 20 insertions. Strategies to overcome C805S should be developed before this acquired resistance becomes a matter of clinical concern. The C797S secondary mutation does not affect ATP competitive inhibition in EGFR-mutated cells. Hence, EGFR-mutated cells with C797S remain sensitive to reversible EGFR TKI [27]. Similarly, C805S did not affect the sensitivity to reversible HER2 TKI. However, this strategy is not applicable to HER2-mutated lung cancer because HER2 exon 20 insertions are inherently resistant to reversible TKIs (Fig. 3D). Alternatively, HSP90 inhibition can be considered as another strategy to cope with HER2 C805S because various RTK products, including HER2/EGFR/ALK, are client proteins of HSP90. Indeed, a HSP90 inhibitor, 17-AAG, exhibits inhibitory activity against the V1180L secondary mutation in the ALK gene [22]. In a previous study, ganetespib showed anti-tumor activity against a mouse model with YVMA, and luminespib downregulated HER2 expression in human tumor xenografts [28,29]. As expected, C805S did not alter sensitivity to the HSP90 inhibitors, ganetespib and luminespib. Therefore, HSP90 inhibitors may be an option for addressing the HER2 C805S secondary mutation, even though disappointing results were obtained in a phase III study of ganetespib for EGFR/ALK-negative pretreated lung adenocarcinoma [30]. According to the literature, the ORRs of NSCLC with HER2 exon 20 insertions treated with EGFR TKIs have been unsatisfactory, except for the treatment of the GSP mutation with dacomitinib (Table 1). [25,[31], [32], [33], [34], [35], [36], [37], [38], [39], [40], [41]]. During the preparation of this manuscript, Robichaux et al. found that poziotinib exhibits potent activity against HER2 exon 20 insertions by comparing the absolute IC50 values of various TKIs [42]. Moreover, these researchers reported a successful treatment of a rare HER2 A771insAYVM with poziotinib. More recently, Oh et al. reported two responders, one with three YVMA and one with two VC, although the number of patients was limited [41]. The results of currently ongoing two phase II trials are eagerly awaited (NCT03066206, NCT033189399).