Convergent Akt activation drives acquired EGFR inhibitor resistance in lung cancer

Jacobsen, Kirstine; Bertrán-Alamillo, Jordi; Molina, Miguel Ángel; Teixidó, Cristina; Karachaliou, Niki; Pedersen, Martin Haar; Castellví, Josep; Garzón, Mónica; Codony-Servat, Carles; Codony-Servat, Jordi; Giménez‐Capitán, Ana; Drozdowskyj, Ana; Viteri, Santiago; Larsen, Martin R.; Lassen, Ulrik; Felip, Enriqueta; Bivona, Trever G.; Ditzel, Henrik J.; Rosell, Rafael

doi:10.1038/s41467-017-00450-6

Cited by 124 publications

(125 citation statements)

References 51 publications

(56 reference statements)

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“…Our data suggest that activation of the PI3K/AKT pathway may be an important compensation mechanism for tumor cell survival after EGFR loss. In agreement with our findings, a recent study showed that Akt activation drives acquired resistance to EGFR-TKI 31 . However, our study further revealed that activated Akt induced by EGFR ablation can be further decreased by elortinib treatment.…”

Section: Discussionsupporting

confidence: 93%

Transcriptional activation of cyclin D1 via HER2/HER3 contributes to cell survival and EGFR tyrosine kinase inhibitor resistance in non-small cell lung carcinoma

Liu

Deng

Chen

et al. 2019

Preprint

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Several different mechanisms are implicated in the resistance of lung cancer cells to epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs), and only few have been functionally investigated. Here, using genetically knocked out EGFR and TKI-resistant lung cancer cells, we show that loss of wild-type EGFR attenuates cell proliferation, migration and 3D-spherid formation, whereas loss of mutant EGFR or resistance to TKIs reinforces those processes. Consistently, disruption of wild-type EGFR leads to suppression of HER2/HER3, while mutant EGFR ablation or resistance to TKIs increases HER2/HER3 expression, compensating for EGFR loss. Furthermore, HER2/HER3 nuclear translocation mediates overexpression of cyclin D1, leading to tumor cell survival and drug resistance. Cyclin D1/CDK4/6 inhibition resensitizes erlotinib-resistant (ER) cells to erlotinib. Analysis of cyclin D1 expression in patients with nonsmall cell lung carcinoma (NSCLC) showed that its expression is negatively associated with overall survival and disease-free survival. Our results provide biological and mechanistic insights into targeting EGFR and TKI resistance.

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Section: Discussionsupporting

confidence: 93%

Transcriptional activation of cyclin D1 via HER2/HER3 contributes to cell survival and EGFR tyrosine kinase inhibitor resistance in non-small cell lung carcinoma

Liu

Deng

Chen

et al. 2019

Preprint

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“…This has led to the development of second-and thirdgeneration irreversible EGFR-TKIs that have also shown outstanding clinical efficacy. Yet studies have shown that cancer cells (and patients) ultimately acquire resistance to these second-and third-generation irreversible EGFR-TKIs, either via acquisition of novel EGFR mutations (C797, L792, or L718) or through bypassing receptor tyrosine kinase signaling by means of a mutation in BRAF or the activation of IGF1R (insulin-like growth factor receptor 1), SRC (SRC protooncogene, nonreceptor tyrosine kinase), FAK/PTK2 (protein tyrosine kinase 2), and YAP (YY1-associated protein 1), which are similar to resistance mechanisms discovered in first-generation EGFR-TKIs (8)(9)(10)(11)(12)(13)(14)(15)(16)(17). Thus, it is important to investigate and understand resistance ABBREVIATIONS: AKR, aldo-keto reductase; ARE, antioxidant-responsive element; CI, combination index; ECM, extracellular matrix; EGFR, epidermal growth factor receptor; EV, empty vector; FACS, fluorescence-activated cell sorting; GR, gefitinib-resistant; IC 50 , half-maximal inhibitory concentration; MTT, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide; NSCLC, non-small cell lung cancer; qRT-PCR, quantitative RT-PCR; TKI, tyrosine kinase receptor mechanisms in EGFR-TKI therapy.…”

mentioning

confidence: 86%

Resistance to gefitinib and cross‐resistance to irreversible EGFR‐TKIs mediated by disruption of the Keap1‐Nrf2 pathway in human lung cancer cells

Park

Kim

et al. 2018

FASEB j.

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The development of resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) occurs by various mechanisms and appears to be almost inevitable, even in patients with lung cancer who initially respond well to EGFR-TKIs. Consequently, considerable efforts have been made to develop more effective EGFR-TKIs. Therefore, an understanding of the mechanisms behind TKI resistance is essential for improving EGFR-TKI therapeutic efficacy in non-small cell lung cancer (NSCLC) patients. In this study, we discovered that overexpression of antioxidant-responsive element (ARE)-containing Nrf2 target genes by increased transactivation of Nrf2 occurred because of an acquired Keap1 mutation in the gefitinib-resistant (GR) NSCLC cell line we established. These GR cells also acquired cross-resistance to the irreversible EGFR-TKIs, afatinib and osimertinib, and showed increased viability, invasiveness, proliferation, and tumorigenicity both in vitro and in vivo. These results were confirmed by the fact that inhibition of Nrf2 activity, either by treatment with brusatol or by inducing expression of exogenously introduced wild-type Keap1, suppressed tumor cell proliferation and tumorigenicity in vitro and in vivo. Our data suggest that disruption of the Keap1-Nrf2 pathway is one of the mechanisms by which EGFR-TKI resistance occurs, a fact that must be considered when treating patients with EGFR-TKI.-Park, S.-H., Kim, J. H., Ko, E., Kim, J.-Y., Park, M.-J., Kim, M. J., Seo, H., Li, S., Lee, J.-Y. Resistance to gefitinib and cross-resistance to irreversible EGFR-TKIs mediated by disruption of the Keap1-Nrf2 pathway in human lung cancer cells.

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“…The importance of Akt activation may also relate to the development of resistance to therapy. Preclinical evidence suggests that Akt activation may confer acquired resistance to EGFR inhibitors in EGFR mutant NSCLC . Similarly mTOR activation has been associated with EGFR and KRAS mutations and may act as a mechanism of resistance to EGFR inhibitors .…”

Section: Importance Of the Pi3k/akt/mtor Pathway In Nsclcmentioning

confidence: 99%

“…Preclinical evidence suggests that Akt activation may confer acquired resistance to EGFR inhibitors in EGFR mutant NSCLC. 59 Similarly mTOR activation has been associated with EGFR and KRAS mutations and may act as a mechanism of resistance to EGFR inhibitors. 60 Given the encompassing downstream signaling effects of the PI3K/Akt/mTOR pathway on the development and progression of malignancy, and its potential influence in response and resistance to standard therapies, it represents an attractive target for anticancer therapy in NSCLC.…”

Section: Importance Of the Pi3k/akt/mtor Pathway In Nsclcmentioning

confidence: 99%

Targeting the PI3K/Akt/mTOR pathway in non‐small cell lung cancer (NSCLC)

2020

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The traditional classification of lung cancer into small cell lung cancer and non‐small cell lung cancer (NSCLC) has been transformed with the increased understanding of the molecular alterations and genomic biomarkers that drive the development of lung cancer. Increased activation of the phosphatidylinositol 3‐kinase (PI3K)/Akt/mechanistic target of rapamycin (mTOR) pathway leads to numerous hallmarks of cancer and this pathway represents an attractive target for novel anticancer therapies. In NSCLC, the PI3K/Akt/mTOR pathway has been heavily implicated in both tumorigenesis and the progression of disease. A number of specific inhibitors of PI3K, Akt and mTOR are currently under development and in various stages of preclinical investigation and in early phase clinical trials for NSCLC. Early evidence has yielded disappointing results. Clinical trials, however, have been performed on predominantly molecularly unselected populations, and patient enrichment strategies using high‐precision predictive biomarkers in future trials will increase the likelihood of success. A greater understanding of the underlying molecular biology including epigenetic alterations is also crucial to allow for the detection of appropriate biomarkers and guide combination approaches.

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Convergent Akt activation drives acquired EGFR inhibitor resistance in lung cancer

Cited by 124 publications

References 51 publications

Transcriptional activation of cyclin D1 via HER2/HER3 contributes to cell survival and EGFR tyrosine kinase inhibitor resistance in non-small cell lung carcinoma

Transcriptional activation of cyclin D1 via HER2/HER3 contributes to cell survival and EGFR tyrosine kinase inhibitor resistance in non-small cell lung carcinoma

Resistance to gefitinib and cross‐resistance to irreversible EGFR‐TKIs mediated by disruption of the Keap1‐Nrf2 pathway in human lung cancer cells

Targeting the PI3K/Akt/mTOR pathway in non‐small cell lung cancer (NSCLC)

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