The quest to overcome resistance to EGFR-targeted therapies in cancer

Chong, Curtis R.; Jänne, Pasi A.

doi:10.1038/nm.3388

Cited by 913 publications

(861 citation statements)

References 191 publications

(166 reference statements)

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“…This indicates an increased and/or prolonged activation of EGFR receptor signalling in ANXA1 knockdown cells. EGFR signalling is known to control several different cellular signalling pathways such as PI3 kinase/AKT, ERK and JAK/STAT signalling pathways [30]. Phosphorylation and activation of STAT3 and AKT was observed in the presence of recombinant EGF in both Ctrl and ANXA1 knockdown cells.…”

Section: Anxa1 Regulates Egfr Signallingmentioning

confidence: 99%

“…Ligand binding results in receptor phosphorylation and activation, although ligandindependent and constitutive EGFR signalling have also been described [28,29]. EGFR activation steers among others JAK/STAT signalling as well as the PI3K/ AKT, the RAS/RAF/ERK and the PLC/PKC pathways controlling processes including DNA repair, proliferation, angiogenesis, and inhibition of apoptosis [30]. Several EGFR-targeting drugs have been developed.…”

Section: Introductionmentioning

confidence: 99%

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Annexin A1 regulates EGFR activity and alters EGFR-containing tumour-derived exosomes in head and neck cancers

Raulf

Lucarelli

Thavaraj

et al. 2018

European Journal of Cancer

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Background: Head and neck squamous cell carcinoma (HNSCC) is the 6th most common cancer with approximately half a million cases diagnosed each year worldwide. HNSCC has a poor survival rate which has not improved for over 30 years. The molecular pathogenesis of HNSCCs remains largely unresolved; there is high prevalence of p53 mutations and EGFR overexpression; however, the contribution of these molecular changes to disease development and/or progression remains unknown. We have recently identified microRNA miR-196a to be highly overexpressed in HNSCC with poor prognosis. Oncogenic miR-196a directly targets Annexin A1 (ANXA1). Although increased ANXA1 expression levels have been associated with breast cancer development, its role in HNSCC is debatable and its functional contribution to HNSCC development remains unclear. Methods: ANXA1 mRNA and protein expression levels were determined by RNA Seq analysis and immunohistochemistry, respectively. Gain-and loss-of-function studies were performed to analyse the effects of ANXA1 modulation on cell proliferation, mechanism of

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Section: Anxa1 Regulates Egfr Signallingmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Annexin A1 regulates EGFR activity and alters EGFR-containing tumour-derived exosomes in head and neck cancers

Raulf

Lucarelli

Thavaraj

et al. 2018

European Journal of Cancer

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“…nonsmall cell lung cancer | EGFR inhibition | tyrosine kinase inhibitors | ERK1/2 paradoxical activation | innate drug resistance L ung cancer is the leading cause of cancer death worldwide (1,2). Of the two major histologic types, small cell and nonsmall cell (NSCLC), the latter is by far the more prevalent (∼85%).…”

mentioning

confidence: 99%

EGFR inhibition evokes innate drug resistance in lung cancer cells by preventing Akt activity and thus inactivating Ets-1 function

Phuchareon

McCormick

Eisele

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Nonsmall cell lung cancer (NSCLC) is the leading cause of cancer death worldwide. About 14% of NSCLCs harbor mutations in epidermal growth factor receptor (EGFR). Despite remarkable progress in treatment with tyrosine kinase inhibitors (TKIs), only 5% of patients achieve tumor reduction >90%. The limited primary responses are attributed partly to drug resistance inherent in the tumor cells before therapy begins. Recent reports showed that activation of receptor tyrosine kinases (RTKs) is an important determinant of this innate drug resistance. In contrast, we demonstrate that EGFR inhibition promotes innate drug resistance despite blockade of RTK activity in NSCLC cells. EGFR TKIs decrease both the mitogen-activated protein kinase (MAPK) and Akt protein kinase pathways for a short time, after which the Ras/MAPK pathway becomes reactivated. Akt inhibition selectively blocks the transcriptional activation of Ets-1, which inhibits its target gene, dual specificity phosphatase 6 (DUSP6), a negative regulator specific for ERK1/2. As a result, ERK1/2 is activated. Furthermore, elevated c-Src stimulates Ras GTP-loading and activates Raf and MEK kinases. These observations suggest that not only ERK1/2 but also Akt activity is essential to maintain Ets-1 in an active state. Therefore, despite high levels of ERK1/2, Ets-1 target genes including DUSP6 and cyclins D1, D3, and E2 remain suppressed by Akt inhibition. Reduction of DUSP6 in combination with elevated c-Src renews activation of the Ras/MAPK pathway, which enhances cell survival by accelerating Bim protein turnover. Thus, EGFR TKIs evoke innate drug resistance by preventing Akt activity and inactivating Ets-1 function in NSCLC cells.nonsmall cell lung cancer | EGFR inhibition | tyrosine kinase inhibitors | ERK1/2 paradoxical activation | innate drug resistance

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“…Current clinical trials are ongoing in order to overcome resistance due to secondary EGFR mutations, which have been observed in several types of cancer [74]. Therefore, targeting various downstream and parallel pathways to inhibit the activation of EGFR in cancer cells is thought to be more efficacious.…”

Section: Clinical Trials Egfr Inhibitor Clinical Trialsmentioning

confidence: 99%

“…Therefore, targeting various downstream and parallel pathways to inhibit the activation of EGFR in cancer cells is thought to be more efficacious. Present clinical trials are also focusing on combinatorial therapies to improve the efficacy of anti-EGFR treatments [74]. Clinical trials involving a combination of oral gemcitabine and erlotinib have been conducted to target EGFR.…”

Section: Clinical Trials Egfr Inhibitor Clinical Trialsmentioning

confidence: 99%

EGFR and c-Met Inhibitors are Effective in Reducing Tumorigenicity in Cancer

Stone¹,

Harrington²,

Frakes³

et al. 2014

J Carcinog & Mutagen

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EGFR and c-Met are receptor tyrosine kinases that are implicated in tumor development and progression in several types of cancer. Both EGFR and c-Met, which are known to be overexpressed and mutated in cancer, share common signaling pathways, including the PI3K/ Akt and MAPK pathways. Small molecule tyrosine kinase inhibitors and monoclonal antibodies that work against EGFR and c-Met are at the forefront of cancer therapy, but their individual efficacies are limited due to the development of drug resistance. In recent pre-clinical studies, we observed that combination therapy using mTOR and Wnt inhibitors with EGFR or c-Met tyrosine kinase inhibitors resulted in overcoming drug resistance. Our studies also indicated that EGFR and c-Met tyrosine kinase inhibitor resistance may be due to activation of alternative signaling pathways. The development of additional combinatorial therapies is underway, and various combinations of inhibitors have shown promising results in clinical trials. Future studies in this direction could be the basis for development of new cancer therapeutics, utilizing EGFR and c-Met inhibitors, which could greatly improve patient prognosis.

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The quest to overcome resistance to EGFR-targeted therapies in cancer

Cited by 913 publications

References 191 publications

Annexin A1 regulates EGFR activity and alters EGFR-containing tumour-derived exosomes in head and neck cancers

Annexin A1 regulates EGFR activity and alters EGFR-containing tumour-derived exosomes in head and neck cancers

EGFR inhibition evokes innate drug resistance in lung cancer cells by preventing Akt activity and thus inactivating Ets-1 function

EGFR and c-Met Inhibitors are Effective in Reducing Tumorigenicity in Cancer

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