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Decoding the EGFR mutation-induced drug resistance in lung cancer treatment by local surface geometric properties
Abstract
Epidermal growth factor receptor (EGFR) mutation-induced drug resistance leads to a limited efficacy of tyrosine kinase inhibitors during lung cancer treatments. In this study, we explore the correlations between the local surface geometric properties of EGFR mutants and the progression-free survival (PFS). The geometric properties include local surface changes (four types) of the EGFR mutants compared with the wild-type EGFR, and the convex degrees of these local surfaces. Our analysis results show that the Spearman׳s rank correlation coefficients between the PFS and three types of local surface properties are all greater than 0.6 with small P-values, implying a high significance. Moreover, the number of atoms with solid angles in the ranges of [0.71, 1], [0.61, 1] or [0.5, 1], indicating the convex degree of a local EGFR surface, also shows a strong correlation with the PFS. Overall, these characteristics can be efficiently applied to the prediction of drug resistance in lung cancer treatments, and easily extended to other cancer treatments.
Keywords: Drug resistance; EGFR mutation; Lung cancer; Alpha shape; Solid angle; Protein surface geometric properties
Results
Figure 1. The 3D alpha shapes. (A) WT EGFR. (B) L858R mutant. (C) Alpha shape surface of the binding sites of WT EGFR. (D) Alpha shape surface of the binding sites of L858R mutant. The major changes around the binding sites compared with WT EGFR are marked with circles. (E) Zooming the two major changes at the left corner of (C). (F) Zooming the two major changes at the left corner of (D).
Figure 2. The relation between the PFS and the four types of local surface changes or the number of (A) reversed, (B) degree-varied, (C) emerged, and (D) disappeared atoms.
Figure 3. Hierarchical clustering of the mutants with PFS and the number of atoms with solid angles in (A) [0.71, 1], (B) [0.61, 1] and (C) [0.5, 1].
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