Clathrin‐mediated EGFR endocytosis as a potential therapeutic strategy for overcoming primary resistance of EGFR TKI in wild‐type EGFR non‐small cell lung cancer

Abstract

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Fluorescence Imaging of Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Resistance in Non-Small Cell Lung Cancer

“…In TKI-responsive cells, Nishimura et al [50] found that endocytosis was inhibited by gefitinib binding, and that the small fraction of receptors that could still internalise were sorted for recycling. Conversely, in gefitinib-resistant cells, EGF-bound wtEGFR did not efficiently progress beyond early endosomes, and gefinitib binding did not inhibit endocytosis in these TKI-resistant cells (these endocytic differences between TKI-sensitive and TKI-resistant cells were recently confirmed [185]). The protein SNX1, a component of the Retromer and part of the trafficking/sorting machinery that targets EGFR to the lysosomes, was found to negatively regulate EGF-dependent EGFR trafficking from early endosomes to late endosomes/lysosomes, and inhibition of SNX1 was shown to underpin TKI resistance [186].…”

“…To investigate the potential effects of endocytosis in the intrinsic resistance to TKIs displayed by ~80% of NSCLC patients with tumours driven by wtEGFR overexpression, Jo et al used wide-field immunofluorescence microscopy to compare the endocytic trafficking of a fluorescent derivative of EGF bound to wtEGFR in NSCLC-derived gefitinib-sensitive H358 cells and gefitinib-resistant H1703 cells [40]. EGF-induced wtEGFR endocytosis was detected in both gefitinib-sensitive and -resistant cells in a clathrin-dependent fashion [40,185]. Only in TKI-sensitive cells were EGF-wtEGFR complexes trafficked beyond early endosomes into recycling endosomes.…”

USP2-Related Cellular Signaling and Consequent Pathophysiological Outcomes

“…In addition to ERBB2, the EGF receptor (EGFR) is also proposed to be controlled by USP2. Surface expression of EGFR is strongly regulated by internalization [64], and the impairment of this endocytic mechanism causes constitutive activation of EGF signaling and carcinogenesis [64,65]. In lung cancer cells, USP2 is distributed to the early endosome, and removes the polyubiquitin chain from internalized EGFR in early endosomes [66].…”

Pyrimidyn‐Based Dynamin Inhibitors as Novel Cytotoxic Agents

“…[22][23][24][25] These enzymes mediate membrane fission during clathrin-mediated endocytosis (CME), [26][27][28] and play additional cellular roles in the exocytic fusion pore, actin dynamics and cytokinesis. [25,[29][30][31] Deficiencies in endocytic pathways are associated with many human pathological conditions such as Alzheimer's disease, Huntington's disease, Stiff-person syndrome, Lewy body dementias and Charcot-Marie-Tooth disease and [23,[32][33][34][35][36][37][38] Dyn II, best known for its role in clathrin-mediated endocytosis, [38,39] acts as a major mitotic hub and plays a pivotal role during cytokinesis, [40][41][42][43][44][45] with its action exquisitely specific, only required for the abscission stage, which results in separation of two daughter cells.…”

“…Mitotic proteins are potentially specific and efficacious anticancer targets. [44][45][46][47][48][49][50] Dynamin inhibitors modulate lamellipodial formation, migration and invasion of human osteocarcinoma cells, inhibit the growth of non-small cell lung carcinoma cells, prostate adenocarcinoma cells and human glioblastoma cells. [43,[51][52][53][54][55][56] Dyn II overexpression is directly associated with poor prognosis in both pancreatic and prostate cancer.…”