Epithelial-mesenchymal transition (EMT) beyond EGFR mutations per se is a common mechanism for acquired resistance to EGFR TKI

Weng, Chien-Hui; Chen, Liyu; Lin, Yu‐Chin; Shih, Jin‐Yuan; Lin, Yun‐Sheng; Tseng, Ruo-Yu; Chiu, An-Chieh; Yeh, Yu-Hsuan; Liu, Chi; Lin, Yuanqing; Fang, Jim‐Min; Chen, Ching-Chow

doi:10.1038/s41388-018-0454-2

Cited by 179 publications

(141 citation statements)

References 48 publications

Supporting

Mentioning

133

Contrasting

Order By: Relevance

“…The Src/FAK network converges on AKT and MAPK to sustain oncogenic signaling and induce EMT. Many of the RTK that signal through Src/FAK have been implicated in EMT-associated resistance to EGFR targeting agents (Tang et al, 2016;Ichihara et al, 2017;Nukaga et al, 2017;Weng et al, 2018).…”

Section: The Role Of Emt In Acquired Resistance To Egfr Tkis Emt Co-omentioning

confidence: 99%

“…Therefore, the use of epigenetic agents may be beneficial to combat phenotypic plasticity as part of acquired drug resistance. Indeed, several histone deacetylate inhibitors (HDACi), including entinostat and trichostatin A, have been shown to restore expression of CDH1 and promote sensitivity to EGFR TKIs in pre-clinical models of EGFR-mutant NSCLC (Sharma et al, 2010;Suda et al, 2011;Weng et al, 2018).…”

Section: Emt In the Absence Of Bypass Activationmentioning

confidence: 99%

See 1 more Smart Citation

Understanding Lineage Plasticity as a Path to Targeted Therapy Failure in EGFR-Mutant Non-small Cell Lung Cancer

et al. 2020

View full text Add to dashboard Cite

Somatic alterations in the epidermal growth factor receptor gene (EGFR) result in aberrant activation of kinase signaling and occur in ∼15% of non-small cell lung cancers (NSCLC). Patients diagnosed with EGFR-mutant NSCLC have good initial clinical response to EGFR tyrosine kinase inhibitors (EGFR TKIs), yet tumor recurrence is common and quick to develop. Mechanisms of acquired resistance to EGFR TKIs have been studied extensively over the past decade. Great progress has been made in understanding two major routes of therapeutic failure: additional genomic alterations in the EGFR gene and activation of alternative kinase signaling (so-called "bypass activation"). Several pharmacological agents aimed at overcoming these modes of EGFR TKI resistance are FDA-approved or under clinical development. Phenotypic transformation, a less common and less well understood mechanism of EGFR TKI resistance is yet to be addressed in the clinic. In the context of acquired EGFR TKI resistance, phenotypic transformation encompasses epithelial to mesenchymal transition (EMT), transformation of adenocarcinoma of the lung (LUAD) to squamous cell carcinoma (SCC) or small cell lung cancer (SCLC). SCLC transformation, or neuroendocrine differentiation, has been linked to inactivation of TP53 and RB1 signaling. However, the exact mechanism that permits lineage switching needs further investigation. Recent reports indicate that LUAD and SCLC have a common cell of origin, and that trans-differentiation occurs under the right conditions. Options for therapeutic targeting of EGFR-mutant SCLC are limited currently to conventional genotoxic chemotherapy. Similarly, the basis of EMT-associated resistance is not clear. EMT is a complex process that can be characterized by a spectrum of intermediate states with diverse expression of epithelial and mesenchymal factors. In the context of acquired resistance to EGFR TKIs, EMT frequently co-occurs with bypass activation, making it challenging to determine the exact contribution of EMT to therapeutic failure. Reversibility of EMT-associated resistance points toward its epigenetic origin, with additional adjustments, such as genetic alterations and bypass activation, occurring later during disease progression. This review will discuss the mechanistic basis for EGFR TKI resistance linked to phenotypic transformation, as well as challenges and opportunities in addressing this type of targeted therapy resistance in EGFR-mutant NSCLC.

show abstract

Section: The Role Of Emt In Acquired Resistance To Egfr Tkis Emt Co-omentioning

confidence: 99%

Section: Emt In the Absence Of Bypass Activationmentioning

confidence: 99%

Understanding Lineage Plasticity as a Path to Targeted Therapy Failure in EGFR-Mutant Non-small Cell Lung Cancer

et al. 2020

View full text Add to dashboard Cite

show abstract

“…Growing evidence has shown that in addition to the T790M mutation and MET amplification, EMT plays an important role in acquired resistance to EGFR-TKIs. EMT is an important process during malignant cancer progression, accompanied by upregulation of N-cadherin and vimentin and downregulation of E-cadherin (30). Furthermore, wound healing and Transwell assays were performed, and the results showed that HCC827GR cells contained high migratory and invasive ability compared with HCC827 cells (Fig.…”

Section: Resultsmentioning

confidence: 94%

The miR‑625‑3p/AXL axis induces non‑T790M acquired resistance to EGFR‑TKI via activation of the TGF‑β/Smad pathway and EMT in EGFR‑mutant non‑small cell lung cancer

Sun

Liu

et al. 2020

Oncol Rep

View full text Add to dashboard Cite

Gefitinib is currently the preferred treatment for non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR)-activating mutation. However, some patients gradually develop acquired resistance after receiving treatment. In addition to secondary T790M mutation, the remaining mechanisms contributing to non-T790M mutations need to be explored. In the present study, NSCLC-derived HCC827 and PC-9 cells and the corresponding gefitinib-resistant cell lines (HCC827GR and PC9GR) were utilized. Next-generation DNA sequencing was performed on the HCC827GR and PC9GR cells. Under AXL receptor tyrosine kinase (AXL) knockdown or miR-625-3p overexpressing conditions, a cell growth inhibition assay was performed to evaluate gefitinib sensitivity. Wound healing and Transwell assays were used to examine the migratory and invasive abilities of the cells. Moreover, we also carried out western blot analysis to detect the altered downstream signaling pathway. Our study revealed markedly decreased miR-625-3p expression in the HCC827GR cell line, while its overexpression partly reversed gefitinib resistance. Integrated analysis based on Targetscan website showed that AXL can be potentially targeted by miR-625-3p and we further verified the hypothesis via dual-luciferase reporter assays. Mechanistic analysis revealed that TGF-β1-induced EMT may contribute to the miR-625-3p/AXL axis-mediated gefitinib resistance. Our data demonstrated that miR-625-3p contributes to the acquired resistance of gefitinib, which may provide novel insight to combat resistance to EGFR-TKIs.Abbreviations: NSCLC, non-small cell lung cancer; TGF-β1, transforming growth factor-β1; HCC827GR, HCC827 gefitinib resistant; EGFR-TKIs, epidermal growth factor receptor-tyrosine kinase inhibitors; EMT, epithelial to mesenchymal transition

show abstract

“…HSP90 is required for the stability and function of numerous oncogenic proteins, and its specific inhibitors display multiple anticancer effects [30][31][32]. On the other hand, Hakai is considered an oncogenic protein that was reported to be overexpressed in various cancers such as colon and lung cancer [16,19,20], furthermore, Hakai knockdown inhibits cell migration [33].…”

Section: Downregulation Of Hakai May Partially Account For the Pharmamentioning

confidence: 99%

Heat Shock Protein 90 Chaperone Regulates the E3 Ubiquitin-Ligase Hakai Protein Stability

Díaz-Díaz

Roca-Lema

Casas-Pais

et al. 2020

Cancers

View full text Add to dashboard Cite

The E3 ubiquitin-ligase Hakai binds to several tyrosine-phosphorylated Src substrates, including the hallmark of the epithelial-to-mesenchymal transition E-cadherin, and signals for degradation of its specific targets. Hakai is highly expressed in several human cancers, including colon cancer, and is considered as a drug target for cancer therapy. Here, we report a link between Hakai and the heat shock protein 90 (Hsp90) chaperone complex. Hsp90 participates in the correct folding of its client proteins, allowing them to maintain their stability and activity. Hsp90 inhibitors specifically interfere with the association with its Hsp90 client proteins, and exhibit potent anti-cancer properties. By immunoprecipitation, we present evidence that Hakai interacts with Hsp90 chaperone complex in several epithelial cells and demonstrate that is a novel Hsp90 client protein. Interestingly, by overexpressing and knocking-down experiments with Hakai, we identified Annexin A2 as a Hakai-regulated protein. Pharmacological inhibition of Hsp90 with geldanamycin results in the degradation of Hakai in a lysosome-dependent manner. Interestingly, geldanamycin-induced Hakai degradation is accompanied by an increased expression of E-cadherin and Annexin A2. We also show that geldanamycin suppresses cell motility at least in part through its action on Hakai expression. Taken together, our results identify Hakai as a novel Hsp90 client protein and shed light on the regulation of Hakai stability. Our results open the possibility to the potential use of Hsp90 inhibitors for colorectal cancer therapy through its action on Hakai client protein of Hsp90.

show abstract

Epithelial-mesenchymal transition (EMT) beyond EGFR mutations per se is a common mechanism for acquired resistance to EGFR TKI

Cited by 179 publications

References 48 publications

Understanding Lineage Plasticity as a Path to Targeted Therapy Failure in EGFR-Mutant Non-small Cell Lung Cancer

Understanding Lineage Plasticity as a Path to Targeted Therapy Failure in EGFR-Mutant Non-small Cell Lung Cancer

The miR‑625‑3p/AXL axis induces non‑T790M acquired resistance to EGFR‑TKI via activation of the TGF‑β/Smad pathway and EMT in EGFR‑mutant non‑small cell lung cancer

Heat Shock Protein 90 Chaperone Regulates the E3 Ubiquitin-Ligase Hakai Protein Stability

Contact Info

Product

Resources

About