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Tyrosine kinase inhibitors for epidermal growth factor receptor (EGFR TKIs) greatly improved clinical outcomes of patients with non-small cell lung cancer (NSCLC). Unfortunately, primary and acquired resistance limits their clinical benefits. To overcome such resistance, new generations of EGFR TKIs have been developed by targeting newly identified mutations in EGFR. However, much less effort has been put into alternative strategies, such as targeting the intrinsic protective responses to EGFR TKIs. In this study, we found that EGFR TKIs, including gefitinib and AZD9291, impaired lysosome-dependent degradation of SQSTM1, thus compromising their anti-cancer efficiency. By accumulating in the lysosome lumen, gefitinib and AZD9291 attenuated lysosomal acidification and impaired autolysosomal degradation of SQSTM1 owing to their intrinsic alkalinity. As a result, SQSTM1 protein was stabilized in response to gefitinib and AZD9291 treatment and conferred EGFR TKI resistance. Depleting SQSTM1 significantly increased the sensitivity of NSCLC cells to gefitinib and AZD9291 both in vitro and in vivo. Furthermore, a chemically modified gefitinib analog lacking alkalinity displayed stronger inhibitory effects on NSCLC cells. Therefore, targeting accumulated SQSTM1 or chemically modified EGFR TKIs may represent new strategies to increase the effectiveness of EGFR targeted therapy.

In this paper, we introduce a new graph operation called subdivision vertex-edge join (denoted by G 1 S ▹ ( G 2 V ∪ G 3 E ) for short), and then the adjacency spectrum, the Laplacian spectrum and the signless Laplacian spectrum of G 1 S ▹ ( G 2 V ∪ G 3 E ) are respectively determined in terms of the corresponding spectra for a regular graph G 1 and two arbitrary graphs G 2 and G 3 . All the above can be viewed as the generalizations of the main results in [X. Liu, Z. Zhang, Bull. Malays. Math. Sci. Soc., 2017:1⁻17]. Furthermore, we also determine the normalized Laplacian spectrum of G 1 S ▹ ( G 2 V ∪ G 3 E ) whenever G i are regular graphs for each index i = 1 , 2 , 3 . As applications, we construct infinitely many pairs of A-cospectral mates, L-cospectral mates, Q-cospectral mates and L -cospectral mates. Finally, we give the number of spanning trees, the (degree-)Kirchhoff index and the Kemeny’s constant of G 1 S ▹ ( G 2 V ∪ G 3 E ) , respectively.