EGFR inhibitors and autophagy in cancer treatment

Cui, Jie; Hu, Yunfeng; Feng, Xie-Min; Tian, Tao; Guo, Ya-Huan; Ma, Junwei; Kang, Nan; Zhang, Hongyi

doi:10.1007/s13277-014-2660-z

Cited by 39 publications

(30 citation statements)

References 73 publications

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“…9,68 In clinical trials, EGFR-TKIs have been used to treat patients with lung cancer 9 and prostate cancer. 57 Although the combination of an anticancer agent with an autophagy inhibitor is designed to synergize cell death of cancer cells, 56,60,61 based on our findings, the same strategy might not be suitable for the combination of an EGFR-TKI and an autophagy inhibitor such as 3-MA or spautin-1.…”

Section: Discussionmentioning

confidence: 99%

“…9 These inhibitors also induce autophagy contributing to cell death. Therefore, we investigated the effect of EGFR-TKIs gefitinib and erlotinib on autophagy and cell death in hypoxia.…”

Section: Egfr Regulates Hypoxia-induced Autophagy and Cell Deathmentioning

confidence: 99%

“…S9C). Since EGFR-TKIs have been used to treat lung cancer patients, 9 we also determined the effects of gefitinib on hypoxia-induced autophagy and cell death in A549 cells. When A549 cells were treated with gefitinib in hypoxia, EGFR tyrosine phosphorylation was inhibited ( Fig.…”

Section: Egfr Regulates Hypoxia-induced Autophagy and Cell Deathmentioning

confidence: 99%

“…[9][10][11][12] EGFR suppresses autophagy in different cell types [12][13][14] through the activation of EGFR which leads to EGFR binding to the autophagy protein BECN1 (Beclin 1, autophagy related) and subsequent tyrosine phosphorylation of BECN1 at multiple sites. This causes the suppression of BECN1-associated PIK3C3 (phosphatidylinositol 3-kinase catalytic subunit type 3) kinase activity and inhibition of autophagy.…”

Section: Introductionmentioning

confidence: 99%

“…[21][22][23][24][25] In response to hypoxia, these tumor cells will either undergo cell death triggered by the expression of proapoptotic proteins such as BNIP3 (BCL2/adenovirus E1B 19kDa interacting protein 3) and TP53 (tumor protein p53) or they will become resistant to chemotherapeutic treatment due to the expression of many procell survival factors including antiapoptotic BCL2 family members and EGFR. 9,25,26 Previous studies including ones from our laboratory have demonstrated that hypoxia can induce autophagy, triggering either a cell survival or cell death response depending upon the context. [27][28][29][30][31][32][33][34][35][36][37][38] A recent study demonstrates that autosis, possibly a subtype of autophagic cell death, is induced by hypoxia-ischemia treatment.…”

Section: Introductionmentioning

confidence: 99%

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Tyrosine kinase receptor EGFR regulates the switch in cancer cells between cell survival and cell death induced by autophagy in hypoxia

et al. 2016

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(2016) Tyrosine kinase receptor EGFR regulates the switch in cancer cells between cell survival and cell death induced by autophagy in hypoxia, Autophagy, 12:6, 1029-1046, DOI: 10.1080/15548627.2016 ABSTRACTAutophagy is an intracellular lysosomal degradation pathway where its primary function is to allow cells to survive under stressful conditions. Autophagy is, however, a double-edge sword that can either promote cell survival or cell death. In cancer, hypoxic regions contribute to poor prognosis due to the ability of cancer cells to adapt to hypoxia in part through autophagy. In contrast, autophagy could contribute to hypoxia induced cell death in cancer cells. In this study, we showed that autophagy increased during hypoxia. At 4 h of hypoxia, autophagy promoted cell survival whereas, after 48 h of hypoxia, autophagy increased cell death. Furthermore, we found that the tyrosine phosphorylation of EGFR (epidermal growth factor receptor) decreased after 16 h in hypoxia. Furthermore, EGFR binding to BECN1 in hypoxia was significantly higher at 4 h compared to 72 h. Knocking down or inhibiting EGFR resulted in an increase in autophagy contributing to increased cell death under hypoxia. In contrast, when EGFR was reactivated by the addition of EGF, the level of autophagy was reduced which led to decreased cell death. Hypoxia led to autophagic degradation of the lipid raft protein CAV1 (caveolin 1) that is known to bind and activate EGFR in a ligand-independent manner during hypoxia. By knocking down CAV1, the amount of EGFR phosphorylation was decreased in hypoxia and amount of autophagy and cell death increased. This indicates that the activation of EGFR plays a critical role in the switch between cell survival and cell death induced by autophagy in hypoxia.

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Section: Discussionmentioning

confidence: 99%

“…9 These inhibitors also induce autophagy contributing to cell death. Therefore, we investigated the effect of EGFR-TKIs gefitinib and erlotinib on autophagy and cell death in hypoxia.…”

Section: Egfr Regulates Hypoxia-induced Autophagy and Cell Deathmentioning

confidence: 99%

Section: Egfr Regulates Hypoxia-induced Autophagy and Cell Deathmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Tyrosine kinase receptor EGFR regulates the switch in cancer cells between cell survival and cell death induced by autophagy in hypoxia

et al. 2016

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Understanding of Autophagy to Combat MDR During Anticancer Therapy

Malviya¹,

Singh²,

Yadav³

2023

Multi‐Drug Resistance in Cancer

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Investigation through naphtho[2,3‐a]pyrene on mutated EGFR mediated autophagy in NSCLC: Cellular model system unleashing therapeutic potential

Samarth,

Gulhane,

Singh

2024

IUBMB Life

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Mutant epidermal growth factor receptor (EGFR) signaling has emerged as a key cause of carcinogenesis and therapy resistance in non‐small cell lung cancer (NSCLC), which continues to pose a serious threat to world health. In this study, we aimed to elucidate the complex molecular pathways of EGFR‐mediated autophagy signaling in NSCLC. We identified naphtho[2,3‐a]pyrene, an anthraquinolone derivative, to be a promising investigational drug that targets EGFR‐mediated autophagy using a cellular model system. By utilizing systems biology, we developed a computational model that explained the signaling of EGFR‐mediated autophagy and identified critical crosstalk sites that could be inhibited therapeutically. As a lead compound, naphtho[2,3‐a]pyrene was confirmed by molecular docking experiments. It was found to be cytotoxic to NSCLC cells, impact migration, induce apoptosis, and arrest cell cycle, both on its own and when combined with standard drugs. The anticancer efficacy of naphtho[2,3‐a]pyrene was validated in vivo on CDX nude mice. It showed synergistic activity against NSCLC when coupled with gefitinib, chloroquine, and radiation. Altogether, our study highlights naphtho[2,3‐a]pyrene's therapeutic promise in NSCLC by focusing on EGFR‐mediated autophagy and providing a new strategy to fight drug resistance and tumor survival.

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EGFR inhibitors and autophagy in cancer treatment

Cited by 39 publications

References 73 publications

Tyrosine kinase receptor EGFR regulates the switch in cancer cells between cell survival and cell death induced by autophagy in hypoxia

Tyrosine kinase receptor EGFR regulates the switch in cancer cells between cell survival and cell death induced by autophagy in hypoxia

Understanding of Autophagy to Combat MDR During Anticancer Therapy

Investigation through naphtho[2,3‐a]pyrene on mutated EGFR mediated autophagy in NSCLC: Cellular model system unleashing therapeutic potential

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