Altered conformational landscape and dimerization dependency underpins the activation of EGFR by
            <i>α</i>
            C–
            <i>β</i>
            4 loop insertion mutations

Ruan, Zheng; Kannan, Natarajan

doi:10.1073/pnas.1803152115

Cited by 60 publications

(71 citation statements)

References 67 publications

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“…Interestingly, we also found that all amino acid changes in our study occurred in a region located after the C‐helix of the EGFR tyrosine kinase domain. Recent studies reported that EGFR exon 20 insertions in this region were constitutive activating mutations . Therefore, this suggested that EGFR exon 20 insertions in SIP may promote epithelial cell proliferation, differentiation, or even malignant transformation.…”

Section: Discussionmentioning

confidence: 99%

“…Recent studies reported that EGFR exon 20 insertions in this region were constitutive activating mutations. 21,22 Therefore, this suggested that EGFR exon 20 insertions in SIP may promote epithelial cell proliferation, differentiation, or even malignant transformation. Future studies are required to evaluate the downstream effects of EGFR exon 20 insertions in SIP.…”

Section: Discussionmentioning

confidence: 99%

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EGFR and KRAS mutations in Chinese patients with sinonasal inverted papilloma and oncocytic papilloma

Wang¹,

Li²,

Hu³

et al. 2019

Histopathology

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Aims Sinonasal inverted papilloma (SIP) and sinonasal oncocytic papilloma (SOP) are uncommon, benign epithelial neoplasms located in the sinonasal region, that have the potential for malignant transformation. A recent study reported that EGFR and KRAS mutations occurred in the majority of Western patients with SIP and SOP, respectively. The aims of this study were to investigate the prevalence of KRAS and EGFR mutations in Chinese SIP and SOP patients, and to study the association between molecular alterations and their clinical features. Methods and results We retrospectively collected 80 sinonasal papilloma specimens, including 44 cases with SIP, 33 cases with SOP, and three cases with mixed sinonasal papilloma, which harboured elements of both inverted and oncocytic types. Formalin‐fixed paraffin‐embedded tissues were used to extract genomic DNA, and EGFR and KRAS mutations were evaluated with direct Sanger sequencing. Thirty‐five (78%) SIP patients harboured EGFR mutations, and all mutations were exon 20 insertions, whereas no KRAS mutations were detected. In contrast, KRAS mutations were detected in 82% of SOP patients, but no EGFR mutations were detected. Among the three mixed‐type cases, two harboured both EGFR exon 20 insertions and KRAS mutations. Another case harboured a KRAS mutation, but no EGFR mutation was detected. Conclusion SIP and SOP are two clinical entities with different genetic mutational patterns of EGFR and KRAS. Mixed types with elements of both SIP and SOP may harbour both EGFR and KRAS mutations.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

EGFR and KRAS mutations in Chinese patients with sinonasal inverted papilloma and oncocytic papilloma

Wang¹,

Li²,

Hu³

et al. 2019

Histopathology

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“…Comparative sequence studies have hypothesized that the αC‐β4 loop is coupled with protein kinase activation by regulating inter‐lobe movement and αC dynamics . Supporting this notion, biophysical and biochemical studies suggest that the αC‐β4 loop maintains auto‐inhibitory interactions to prevent inadvertent kinase activation .…”

Section: Disease Variants In the αC‐β4 Loopmentioning

confidence: 99%

“…Extended αC‐β4 loops are most commonly found in the CK1 and CMGC groups (Figure a) usually in the form of a short helical insert (Figure b). In many cases, extended αC‐β4 loops seem to be linked to constitutive enzyme activity . Table shows a list of kinases containing an extended αC‐β4 loop.…”

Section: Conservation and Variation In The αC‐β4 Loop Of Protein Kinasesmentioning

confidence: 99%

Emerging roles of the αC‐β4 loop in protein kinase structure, function, evolution, and disease

2020

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The faithful propagation of cellular signals in most organisms relies on the coordinated functions of a large family of protein kinases that share a conserved catalytic domain. The catalytic domain is a dynamic scaffold that undergoes large conformational changes upon activation. Most of these conformational changes, such as movement of the regulatory αC-helix from an "out"to "in" conformation, hinge on a conserved, but understudied, loop termed the αC-β4 loop, which mediates conserved interactions to tether flexible structural elements to the kinase core. We previously showed that the αC-β4 loop is a unique feature of eukaryotic protein kinases. Here, we review the emerging roles of this loop in kinase structure, function, regulation, and diseases. Through a kinome-wide analysis, we define the boundaries of the loop for the first time and show that sequence and structural variation in the loop correlate with conformational and regulatory variation. Many recurrent disease mutations map to the αC-β4 loop and contribute to drug resistance and abnormal kinase activation by relieving key auto-inhibitory interactions associated with αC-helix and interlobe movement. The αC-β4 loop is a hotspot for post-translational modifications, protein-protein interaction, and Hsp90 mediated folding. Our kinome-wide analysis provides insights for hypothesis-driven characterization of understudied kinases and the development of allosteric protein kinase inhibitors.

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“…Patients with other, less common-activating mutations such as exon 20 insertions show no benefit from EGFR TKIs (see e.g. mycancergenome.org) despite EGFR being effectively dephosphorylated [8-10]. Apart from this mutation-specificity, there also a drug-specificity of clinical responses: where several EGFR-TKIs (erlotinib, gefitinib, afatinib, dacomitinib and osimertinib) have provided clinical benefit to EGFR -mutated pulmonary adenocarcinoma patients, a phase II study on lapatinib did not show any sign of clinical activity [10-12].…”

Section: Introductionmentioning

confidence: 99%

Effective Tyrosine Kinase Inhibitors result in the intracellular accumulation of EGFR and allows response prediction in patients

Gao

Mercieca

et al. 2019

Preprint

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Clinical responses to EGFR tyrosine kinase inhibitors are restricted only to tumors harboring specific activating mutations and even then, not all tyrosine kinase inhibitors provide clinical benefit. We here show that the addition of EGFR-TKIs results in a strong and rapid intracellular accumulation of the protein. However, this accumulation was observed only in the context of a combination of a TKI-sensitive mutation with a clinically effective TKI: TKI-insensitive mutations did not show this accumulation nor did clinically ineffective TKIs induce accumulation. All TKIs effectively inhibited EGFR phosphorylation and downstream pathway activation, irrespective of the mutation present in EGFR. The discrepancy between molecular activity of TKIs and their efficacy in patients therefore is mimicked by the mutation- and TKI-specificity of intracellular accumulation. Using this intracellular accumulation as assay, we were able to predict response to gefitinib in a panel of cell-lines (harboring different EGFR mutations) and predicted clinical benefit to EGFR TKIs on a cohort of unselected pulmonary adenocarcinoma patients (hazard ratio 0.21, P=0.0004). Even in patients harboring rare mutations with unknown TKI-sensitivity, intracellular accumulation was predictive of the clinical response. The intracellular accumulation depended on a continued presence of TKI indicating that TKIs exert a continued effect on the protein even after its dephosphorylation. It is therefore possible that accumulation is caused by conformational changes induced by both the mutation and the TKI and this change induces a block in intracellular trafficking. Interestingly, intracellular accumulation was observed independent of the genetic background of the cell, indicating that accumulation is almost entirely dictated by the combination of mutation and TKI. Our results therefore suggest that TKI-sensitivity is tumor-type independent.

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Altered conformational landscape and dimerization dependency underpins the activation of EGFR by α C– β 4 loop insertion mutations

Cited by 60 publications

References 67 publications

EGFR and KRAS mutations in Chinese patients with sinonasal inverted papilloma and oncocytic papilloma

EGFR and KRAS mutations in Chinese patients with sinonasal inverted papilloma and oncocytic papilloma

Emerging roles of the αC‐β4 loop in protein kinase structure, function, evolution, and disease

Effective Tyrosine Kinase Inhibitors result in the intracellular accumulation of EGFR and allows response prediction in patients

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