TIP30 overcomes gefitinib resistance by regulating cytoplasmic and nuclear EGFR signaling in non–small‐cell lung cancer

Shuai, Shuai; Liao, Xin‐Hua; Wang, Haixia; Liu, Lusha; Mei, Shiqi; Cao, Jia-Xin; Wang, Senming

doi:10.1111/cas.15000

Cited by 6 publications

(5 citation statements)

References 40 publications

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“…Lysosomal degradation of EGFR has been reported as a mechanism of NSCLC suppression by both endogenous signaling pathways and putative therapeutics (37)(38)(39). Indeed, restoration of lysosomal degradation has been reported to overcome EGFR TKI resistance both in vitro and in mouse models of NSCLC, and represents a promising mechanism for EGFR-directed therapeutics (40,41).…”

Section: Discussionmentioning

confidence: 99%

A molecularly engineered lectin destroys EGFR and inhibits the growth of non-small cell lung cancer

Chan,

Raglow,

Pal

et al. 2024

Preprint

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Survival rates for non-small cell lung cancer (NSCLC) remain low despite the advent of novel therapeutics. Tyrosine kinase inhibitors (TKIs) targeting mutant epidermal growth factor receptor (EGFR) in NSCLC have significantly improved mortality but are plagued with challenges — they can only be used in the small fraction of patients who have susceptible driver mutations, and resistance inevitably develops. Aberrant glycosylation on the surface of cancer cells is an attractive therapeutic target as these abnormal glycosylation patterns are typically specific to cancer cells and are not present on healthy cells. H84T BanLec (H84T), a lectin previously engineered by our group to separate its antiviral activity from its mitogenicity, exhibits precision binding of high mannose, an abnormal glycan present on the surface of many cancer cells, including NSCLC. Here, we show that H84T binds to and inhibits the growth of diverse NSCLC cell lines by inducing lysosomal degradation of EGFR and leading to cancer cell death through autophagy. This is a mechanism distinct from EGFR TKIs and is independent of EGFR mutation status; H84T inhibited proliferation of both cell lines expressing wild type EGFR and those expressing mutant EGFR that is resistant to all TKIs. Further, H84T binds strongly to multiple and diverse clinical samples of both pulmonary adenocarcinoma and squamous cell carcinoma. H84T is thus a promising potential therapeutic in NSCLC, with the ability to circumvent the challenges currently faced by EGFR TKIs.

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Section: Discussionmentioning

confidence: 99%

A molecularly engineered lectin destroys EGFR and inhibits the growth of non-small cell lung cancer

Chan,

Raglow,

Pal

et al. 2024

Preprint

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“…HTATIP2 expression is frequently down-regulated in cancers ( 36 , 45 ), which is in agreement with our result that knock-down increases T cell proliferation in the absence of exogenous growth signals. HTATIP2 affects signaling by the epidermal growth factor receptor by regulating endocytosis and EGFR signaling from endosomes ( 43 , 46 , 47 ). Another facet of HTATIP2’s role in subcellular trafficking is in transport of proteins between the nucleus and cytoplasm by interaction with the nuclear pore complex ( 41 , 48 ).…”

Section: Discussionmentioning

confidence: 99%

Genome-wide association study of the age of onset of type 1 diabetes reveals HTATIP2 as a novel T cell regulator

et al. 2023

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IntroductionType 1 diabetes, a disorder caused by autoimmune destruction of pancreatic insulin-producing cells, is more difficult to manage when it presents at a younger age. We sought to identify genetic correlates of the age of onset by conducting the first genome-wide association study (GWAS) treating the age of first diagnosis as a quantitative trait.MethodsWe performed GWAS with a discovery cohort of 4,014 cases and a replication cohort of 493 independent cases. Genome-wide significant SNPs were mapped to a causal variant by Bayesian conditional analysis and gel shift assay. The causal protein-coding gene was identified and characterized by RNA interference treatment of primary human pan-CD4+ T cells with RNA-seq of the transcriptome. The candidate gene was evaluated functionally in primary cells by CD69 staining and proliferation assays.ResultsOur GWAS replicated the known association of the age of diagnosis with the human leukocyte antigen complex (HLA-DQB1). The second signal identified was in an intron of the NELL1 gene on chromosome 11 and fine-mapped to variant rs10833518 (P < 1.54 × 10−9). Homozygosity for the risk allele leads to average age of onset one year earlier. Knock-down of HIV TAT-interacting protein 2 (HTATIP2), but not other genes in the locus, resulted in alterations to gene expression in signal transduction pathways including MAP kinases and PI3-kinase. Higher levels of HTATIP2 expression are associated with increased viability, proliferation, and activation of T cells in the presence of signals from antigen and cytokine receptors.DiscussionThis study implicates HTATIP2 as a new type 1 diabetes gene acting via T cell regulation. Larger population sample sizes are expected to reveal additional loci.

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“…Negative regulatory effects of HTATIP2 have been reported for UV‐induced DNA damage repair, affecting respective relevant DNA repair pathways [ 46 ]. Other reports implicated HTATIP2 expression in membrane‐cytoplasmic trafficking, resulting in modulation of EGFR signaling [ 47 ], and the potential of HTATIP2 overexpression to overcome resistance to the tyrosine kinase inhibitor gefitinib in nonsmall cell lung cancer cells by interfering with EGFR signaling [ 48 ].…”

Section: Discussionmentioning

confidence: 99%

Epigenetic silencing of HTATIP2 in glioblastoma contributes to treatment resistance by enhancing nuclear translocation of the DNA repair protein MPG

et al. 2023

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Glioblastoma, the most malignant brain tumor in adults, exhibits characteristic patterns of epigenetic alterations that await elucidation. The DNA methylome of glioblastoma revealed recurrent epigenetic silencing of HTATIP2, which encodes a negative regulator of importin β‐mediated cytoplasmic–nuclear protein translocation. Its deregulation may thus alter the functionality of cancer‐relevant nuclear proteins, such as the base excision repair (BER) enzyme N‐methylpurine DNA glycosylase (MPG), which has been associated with treatment resistance in GBM. We found that induction of HTATIP2 expression in GBM cells leads to a significant shift of predominantly nuclear to cytoplasmic MPG, whereas depletion of endogenous HTATIP2 results in enhanced nuclear MPG localization. Reduced nuclear MPG localization, prompted by HTATIP2 expression or by depletion of MPG, yielded less phosphorylated‐H2AX‐positive cells upon treatment with an alkylating agent. This suggested reduced MPG‐mediated formation of apurinic/apyrimidinic sites, leaving behind unrepaired DNA lesions, reflecting a reduced capacity of BER in response to the alkylating agent. Epigenetic silencing of HTATIP2 may thus increase nuclear localization of MPG, thereby enhancing the capacity of the glioblastoma cells to repair treatment‐related lesions and contributing to treatment resistance.

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TIP30 overcomes gefitinib resistance by regulating cytoplasmic and nuclear EGFR signaling in non–small‐cell lung cancer

Cited by 6 publications

References 40 publications

A molecularly engineered lectin destroys EGFR and inhibits the growth of non-small cell lung cancer

A molecularly engineered lectin destroys EGFR and inhibits the growth of non-small cell lung cancer

Genome-wide association study of the age of onset of type 1 diabetes reveals HTATIP2 as a novel T cell regulator

Epigenetic silencing of HTATIP2 in glioblastoma contributes to treatment resistance by enhancing nuclear translocation of the DNA repair protein MPG

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