Abstract
In the past decades, epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) had been proved as an effective treatment strategy for the patients with EGFR-mutated non-small-cell lung cancer (NSCLC). However, the tolerance for the EGFR-TKI always occurred after continuous administration for a period of time and limiting the application of these drugs. Activation of FGFR1 signaling pathway was one of the important escape mechanisms for EGFR-TKI resistant in NSCLC. Here, a novel dual inhibitor of EGFRL858R/T790M and FGFR1, compound15c, was found and can efficiently overcame the EGFR-TKI resistance via its simultaneous inhibition of their kinase activities. Comparison with EGFRL858R/T790M and FGFR1 inhibitor treatment alone or combined revealed that the inhibition of EGFRL858R/T790M and FGFR1 activity by 15c was responsible for surmounting the intrinsic EGFR-TKI resistance in EGFRL858R/T790M-mutated H1975 cells and the acquired resistance in Afatinib-tolerant PC9 cells (AFA-PC9). Flow Cytometry and Caspase3 activity analysis assay showed that 15c induced significant the early apoptosis of H1975 cells. Xenograft tumor formation in BALB/c mice induced by a H1975 cells was suppressed by 15c treatment, with no changes in animal body weight. Generally, 15c may act as a new-generation EGFR-TKI for the therapy of NSCLC patients suffering a resistance to current TKI.
Highlights
In the past few decades, to improve therapeutic activity and selectivity while developing antitumor drugs is always a great challenge
We suggest that 15c may act as a new-generation epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) for the therapy of non-small-cell lung cancer (NSCLC) patients suffering a resistance to current TKI
In order to explore whether those compounds can inhibit the FGFR1 kinase activity, all the compounds were measured the kinase inhibitory effect against EGFRWT, EGFRL858R/T790M, and FGFR1WT in a cell-free system called Caliper Mobility Shift Assay
Summary
In the past few decades, to improve therapeutic activity and selectivity while developing antitumor drugs is always a great challenge. Several first-generation EGFR-targeted TKIs, such as Erlotinib and Gefitinib, had been approved by U.S FDA for the treatment of NSCLC patients that harbor activating mutations in the EGFR (L858R or delE746-A750) (Cohen et al, 2003; Cohen et al, 2005; Cataldo et al, 2011). Resistance to those inhibitors can be acquired due to secondary mutations (Bean et al, 2007; Kuang et al, 2009). Unlike the widely reported cMet and IGF-1R, the FGFR-dependent signaling act as an escape mechanism for EGFR-TKI resistance still have long way to go (Kono et al, 2009)
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