EGFR Tyrosine Kinase Inhibitors Activate Autophagy as a Cytoprotective Response in Human Lung Cancer Cells

Abstract

Epidermal growth factor receptor tyrosine kinase inhibitors gefitinib and erlotinib have been widely used in patients with non-small-cell lung cancer. Unfortunately, the efficacy of EGFR-TKIs is limited because of natural and acquired resistance. As a novel cytoprotective mechanism for tumor cell to survive under unfavorable conditions, autophagy has been proposed to play a role in drug resistance of tumor cells. Whether autophagy can be activated by gefitinib or erlotinib and thereby impair the sensitivity of targeted therapy to lung cancer cells remains unknown. Here, we first report that gefitinib or erlotinib can induce a high level of autophagy, which was accompanied by the inhibition of the PI3K/Akt/mTOR signaling pathway. Moreover, cytotoxicity induced by gefitinib or erlotinib was greatly enhanced after autophagy inhibition by the pharmacological inhibitor chloroquine (CQ) and siRNAs targeting ATG5 and ATG7, the most important components for the formation of autophagosome. Interestingly, EGFR-TKIs can still induce cell autophagy even after EGFR expression was reduced by EGFR specific siRNAs. In conclusion, we found that autophagy can be activated by EGFR-TKIs in lung cancer cells and inhibition of autophagy augmented the growth inhibitory effect of EGFR-TKIs. Autophagy inhibition thus represents a promising approach to improve the efficacy of EGFR-TKIs in the treatment of patients with advanced non-small-cell lung cancer.

YY1-MIR372-SQSTM1 regulatory axis in autophagy

“…Meanwhile, blocking autophagy with either the lysosomal inhibitor chloroquine or ATG7 siRNAs strongly enhances the apoptosis induced by various anticancer agents such as tyrosine kinase inhibitors. [20][21][22][23] SQSTM1, a member of the autophagic receptors that promote autophagy activation, is highly expressed in many human cancers. [24][25][26] In addition, accumulation of SQSTM1 promotes tumorigenesis while inhibition of autophagy prevents tumor growth in nude mice.…”

mTORC1-independent autophagy regulates receptor tyrosine kinase phosphorylation in colorectal cancer cells via an mTORC2-mediated mechanism

“…EGFR targeted therapy has been characterised as a potent autophagy-inducing stimulus in cancer cells 17,19,42,44,45,[48][49][50] Interestingly, we found that all CRC cell lines utilised in this work exhibit basal autophagic flux irrespective of their PI3K or KRAS mutational status. Although earlier studies have suggested that autophagy can be regulated in an mTORC1-independent manner, [13][14][15][16][17][18][19] the role of basal autophagy in cancer remains elusive.…”

“…It has been proposed by us and others that in established tumours autophagy plays a pro-survival role, 28,39,41,42,45,46,57 in particular upon starvation or downstream inhibition of oncogenic kinase signalling, both of which result in inhibition of the main autophagy inhibitor, the PI3K/AKT/mTORC1 pathway. However, little is known on the role of autophagy and autophagy-like pathways in the presence of active PI3K/AKT/mTORC1 signalling in cancer cells, due to mutations in either PI3K or RAS pathway.…”

“…28,39,41,42,45,46 We set out to further investigate the RTK-autophagy pathway in the context of CRC, where RTK signalling is a factor implicated in tumour development and is being targeted clinically. In particular, several agents targeting EGFR and other members of the ErbB family are currently being tested in CRC trials.…”

“…In turn, pharmacological inhibition of autophagy potentiates OncTK/RTK targeted therapy. 2,28,[38][39][40][41] In particular, autophagy has been placed downstream of two RTKs with a known role in cancer, the Epidermal Growth Factor Receptor (EGFR) 17,19,[42][43][44][45][46][47][48][49][50] and the Hepatocyte Growth Factor Receptor (HGFR), c-MET. 51 EGFR has been suggested to regulate autophagy either directly 17,19 or indirectly through its downstream effectors.…”