The Relative Expression of Mig6 and EGFR Is Associated with Resistance to EGFR Kinase Inhibitors

Chang, Xiaofei; Izumchenko, Eugene; Solis, Luisa M.; Kim, Myoung Sook; Chatterjee, Aditi; Ling, Shizhang; Monitto, Constance L.; Harari, Paul M.; Hidalgo, Manuel; Goodman, Steven N.; Wistuba, Ignacio I.; Bedi, Atul; Sidransky, David

doi:10.1371/journal.pone.0068966

Cited by 37 publications

(47 citation statements)

References 34 publications

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“…We evaluated pairs of cancer cell lines with wild type EGFR that were either sensitive or resistant to the EGFR TKI, erlotinib; lung carcinoma (H358/H1703 and Calu3/Calu6) and H&N cancer (SCC-S/SCC-R and JHU011/JHU028). Erlotinib-resistant (SCC-R) and erlotinib-sensitive (SCC-S) isogenic cell lines were generated by chronic exposure of human H&N squamous cell carcinoma UM-SCC1 cells to either erlotinib or DMSO (vehicle control) (24). The other three pairs of cell lines (JHU011/JHU028, H358/H1703 and Calu3/Calu6) are intrinsically erlotinib-sensitive or erlotinib-resistant.…”

Section: Resultsmentioning

confidence: 99%

“…Drug resistant cell-lines were generated via a process of slowly escalating exposure to erlotinib, as reported previously (24). SCC-S is used to designate the parental UM-SCC1 cells exposed to DMSO, and SCC-R refers to the erlotinib resistant clone.…”

Section: Methodsmentioning

confidence: 99%

“…We recently reported that EGFR activity was markedly decreased during acquired resistance to the EGFR TKI erlotinib, with a concomitant increase of Mig6 through the activation of the PI3K-AKT pathway. A low Mig6/EGFR ratio was highly correlated with erlotinib sensitivity in a panel of cancer cell lines and early passage xenografts of human tumors with wild type EGFR (24). …”

Section: Introductionmentioning

confidence: 99%

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The TGFβ–miR200–MIG6 Pathway Orchestrates the EMT-Associated Kinase Switch That Induces Resistance to EGFR Inhibitors

et al. 2014

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While specific mutations in the tyrosine kinase domain of epidermal growth factor receptor (EGFR) identify tumors that are responsive to EGFR tyrosine kinase inhibitors (TKIs), these genetic alterations are present in only a minority of patients. Patients with tumors expressing wild-type (wt) EGFR lack reliable predictive markers of their clinical response to EGFR TKIs. Although epithelial-mesenchymal transition (EMT) has been inversely correlated with the response of cancers to EGFR-targeted therapy, the precise molecular mechanisms underlying this association have not been defined and no specific EMT-associated biomarker of clinical benefit has been identified. Here we show that during transforming growth factor-β (TGFβ)-mediated EMT, inhibition of the microRNAs 200 (miR200) family results in upregulated expression of mitogen-inducible gene 6 (Mig6), a negative regulator of EGFR. The Mig6-mediated reduction of EGFR occurs concomitantly with a TGFβ-induced EMT-associated kinase switch of tumor cells to an AKT-activated EGFR-independent state. In a panel of 25 cancer cell lines of different tissue origins, we find that the ratio of the expression levels of Mig6 and miR200c is highly correlated with EMT and resistance to erlotinib. Analyses of primary tumor xenografts of patient-derived lung and pancreatic cancers carrying wild type EGFR showed that the tumor Mig6(mRNA)/miR200 ratio was inversely correlated with response to erlotinib in vivo. Our data demonstrate that the TGFβ-miR200-Mig6 network orchestrates the EMT-associated kinase switch that induces resistance to EGFR inhibitors, and identify a low ratio of Mig6 to miR200 as a promising predictive biomarker of the response of tumors to EGFR TKIs.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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The TGFβ–miR200–MIG6 Pathway Orchestrates the EMT-Associated Kinase Switch That Induces Resistance to EGFR Inhibitors

et al. 2014

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“…A recent study evaluated the relative expression level of MIG6 and EGFR in a small cohort of lung cancer patients treated prospectively with gefitinib. This study concluded that a lower MIG6/EGFR ratio is associated with sensitivity to TKIs, whereas a higher MIG6/EGFR ratio is a predictor of TKI resistance (56). In another study, ratio of MIG6 and miR200c RNA levels correlated with EMT and resistance to erlotinib (57).…”

Section: Discussionmentioning

confidence: 99%

Loss of MIG6 Accelerates Initiation and Progression of Mutant Epidermal Growth Factor Receptor–Driven Lung Adenocarcinoma

et al. 2015

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Somatic mutations in the epidermal growth factor receptor (EGFR) kinase domain drive lung adenocarcinoma. We have previously identified MIG6, an inhibitor of ERBB signaling and a potential tumor suppressor, as a target for phosphorylation by mutant EGFRs. Here we demonstrate that Mig6 is a tumor suppressor for the initiation and progression of mutant EGFR-driven lung adenocarcinoma in mouse models. Mutant EGFR-induced lung tumor formation was accelerated in Mig6-deficient mice, even with Mig6 haploinsufficiency. We demonstrate that constitutive phosphorylation of MIG6 at Y394/395 in EGFR-mutant human lung adenocarcinoma cell lines is associated with an increased interaction of MIG6 with mutant EGFR, which may stabilize EGFR protein. MIG6 also fails to promote mutant EGFR degradation. We propose a model whereby increased tyrosine phosphorylation of MIG6 decreases its capacity to inhibit mutant EGFR. Nonetheless, the residual inhibition is sufficient for Mig6 to delay mutant EGFR-driven tumor initiation and progression in mouse models.

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“…[22][23][24][25] It is possible, of course, that the two footprints were separated in evolutionary time, with the 3 0 -tigger footprint resulting from a gene conversion involving the nascent SH3-MHC gene, e.g., via an ABL kinase exchange with a GTPaselike gene harboring the nascent NefL structures. [26][27][28] Finally, the inherent resistance of C. atys to SIV disease, [29][30][31] suggests that some biology linked to the Loc-105576907 orf might afford novel explanations, and quite possibly novel approaches to HIV-1 therapeutics. The T. syrichta Loc-103275158 orf is (as we have discussed) one such piece of biology.…”

Section: Gov) H (Helix) Hth (Helix-turn-helix) Hss (Helix-strand-smentioning

confidence: 99%

TE-domestication and horizontal transfer in a putative Nef-AP1mu mimic of HLA-A cytoplasmic domain re-trafficking

Murray¹,

Murray²

2016

Mobile Genetic Elements

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Genes of the major histocompatibility complex (MHC; also called HLA in human) are polymorphic elements in the genomes of sharks to humans. Class-I and class-II MHC loci appear responsible for much of the genetic linkage to myriad disease states via the capacity to bind short (~8-15 a.a.) peptides of a given pathogen's proteome, or in some cases, the altered proteomes of cancerous cells, and even (in autoimmunity) certain nominal 'self' peptides (Janeway, 2004).1 Unfortunately, little is known about how the canonical structure of the MHC-I/-II peptide-presenting gene evolved, particularly since beyond~500 Mya (sharks) no paralogs exist.2, 3 We previously reported that HLA-A isotype alleles with the a1-helix, R65 motif, are wide-spread in phylogeny, but that the a 2-helix, H151R motif, has apparently segregated out of most species. Surprisingly, an uncharacterized orf in T. syrichta (Loc-103275158) encoded R151, but within a truncated A-23 like gene containing 5 0 -and 3 0 -footprints of the transposon (TE), tigger-1; the extant tarsier A-23 allele is totally missing exon-3 and part-of exon-4; together, suggesting TE-mediated inactivation of an intact/ancestral A-23 allele (Murray, 2015a). 4 The unique Loc-103275158 orf encodes a putative 15-exon transcript with no apparent paralogs throughout phylogeny. However, an HLA-A11 like gene in M. leucophaeus with a shortened C-terminal domain, and an HLA-A like orf in C. atys with two linked a1/a2/a3 domains, both contain a second transmembrane segment, which is conserved in Loc-103275158. Thus, we could model the putative protein with its Nef-like tail domain docked to its MHC-I like a3 domain (i.e., on the same side of a membrane). This modeled tertiary structure is strikingly similar to the solved structure of the Nef:MHC-I CD:AP1mu transporter (Jia, 2012).5 Nef:AP1mu binds the CD of MHC-I in trafficking MHC-I away from the trans-golgi and into the endocytic pathway in HIV-1 infected cells. The CD loop of the Loc-103275158 provisional protein conserved the nominal MHC-I CD tyrosine phosphorylation site, and it has an N-terminal SH3 domain that we docked in one conformation to its internal Nef-like domain. Here, we suggest that phosphorylation of the protein's CD-loop signals an exchange between the internal Nef-like domain and a lentiviral-Nef for binding the N-terminal SH3 domain -freeing the Nef-like domain to bind MHC-I CD. Since the 5 0 -tigger sequence encodes part of the pseudo a1/a2 MHC-I domain, and the 3 0 -tigger part of the Nef-like domain, we speculate that transposition proceeded phylogenetically disparate horizontal transfers, involving adjacent 5 0 -and 3 0 -parasitic footprints, which we also found in the Loc-103275158 orf.

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The Relative Expression of Mig6 and EGFR Is Associated with Resistance to EGFR Kinase Inhibitors

Cited by 37 publications

References 34 publications

The TGFβ–miR200–MIG6 Pathway Orchestrates the EMT-Associated Kinase Switch That Induces Resistance to EGFR Inhibitors

The TGFβ–miR200–MIG6 Pathway Orchestrates the EMT-Associated Kinase Switch That Induces Resistance to EGFR Inhibitors

Loss of MIG6 Accelerates Initiation and Progression of Mutant Epidermal Growth Factor Receptor–Driven Lung Adenocarcinoma

TE-domestication and horizontal transfer in a putative Nef-AP1mu mimic of HLA-A cytoplasmic domain re-trafficking

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