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  • The role of other FGFR family members in


    The role of other FGFR family members in EGFR inhibition resistance has been described in several published works, with FGFR1/FGFR2 upregulation as well as FGFR3 mutations known to be resistance mechanisms to anti-EGFR therapy [[31], [32], [33], [34], [35]], for which the combined use of EGFR and FGFR inhibitors has been proposed. Indeed, the inhibition of FGFR2 causes increased sensitivity to erlotinib in vitro in some lung cancer models [36]. However, we are the first to describe such a role for FGFR4. In addition, the previous studies were focused mainly on the role of these FGFRs in acquired resistance after EGFR inhibitor treatment. Nonetheless, we show that FGFR4 overexpression can occur in tumors before their exposure to EGFR inhibitors, leading to intrinsic anti-EGFR therapy resistance, as our patient cohort had not received previous EGFR inhibition therapy. Taken together, these findings suggest a potential close interaction between EGFR and FGFRs, which may be interesting to explore in order to identify other FGFRs in different tumoral settings. At the therapeutic level, the logical approach to address the cooperation between FGFR4 and EGFR was the combined inhibition of both receptors. To explore the potential efficacy and specificity of this approach, we tested the effect of FGFR and EGFR inhibitors in monotherapy or in combination in syngeneic models with FGFR4 overexpression in vitro and in vivo. We found that the combined inhibition showed superior and dramatic effects in terms of proliferation or tumor growth than when either inhibitor was used alone, especially in models with induced FGFR4 expression, thereby demonstrating the potential efficacy of this combined treatment in EGFR-activated, FGFR4-expressing tumors. These results suggest that dual EGFR/FGFR inhibition may serve as a potentially effective therapy for patients with high EGFR activation and FGFR4 expression.
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    Authors' contributions
    Introduction Detection of driver mutations in patients with advanced non-small cell lung cancer (NSCLC) is critical because they receive great benefit from kinase inhibitors [[1], [2], [3], [4]]. However, it AMG 925 is often difficult to obtain tumor tissue in advanced NSCLC patients. Cell-free DNA (cfDNA) from peripheral blood is a useful material to solve this problem. In epidermal growth factor receptor (EGFR) mutated patients, several studies demonstrated that plasma samples could be a substitute for tumor tissue in analyzing EGFR mutation [5,6]. Moreover, cfDNA analysis using cobas® EGFR mutation kit version.2 (Roche Molecular Diagnostics, Inc, CA) has already been introduced into clinical practice. Beyond this diagnostic approach, liquid biopsy may be an ideal method to monitor the genetic status of cancer during treatment because it can be done less invasively and repeatedly. Although several studies have already shown the feasibility of monitoring EGFR mutations in each patient [7,8], most of them focused on representative cases. Thus, as the statement paper suggested, it has not been proven whether sequential cfDNA monitoring is clinically meaningful or not, and also it has not been elucidated which patients are benefit from this approach [9]. Previously, we reported the establishment of multiplexed assay of three EGFR mutations (exon 19del, exon 20 T790 M and exon 21 L858R) using highly sensitive digital PCR [10]. Based on this, we conducted a multi-institutional biomarker study of EGFR mutated patients who were treated with afatinib (West Japan Oncology Group (WJOG) 8114LTR).
    Materials and methods
    Results Between February and December 2015, 57 patients were registered in the study. Clinical characteristics of the registered patients are shown in Table 1. Of those, 31 (53%) were female. Thirty-nine patients (68%) were stage IV and 16 (28%) were post-operative relapse. Number of each EGFR mutation (exon 19del and exon 21 L858R) of the patients were almost the same. After registration, two patients did not receive protocol treatment due to acute interstitial lung disease and rapid disease progression. Thus, 55 patients were recognized per protocol set and were analyzed for their efficacy and safety. Overall response rate was 78.6% (95% confidence interval (CI): 67.3–89.1%) and median PFS was 14.2 months (95%CI: 10.5–19.1 months). Profiles and severity of adverse events (data not shown) were similar to the pivotal study [12]. During study treatment, one patient died in a traffic accident; this event was considered unrelated to study treatment.