Gene copy number variation and protein overexpression of EGFR and HER2 in distal extrahepatic cholangiocarcinoma

Jung, Min-Jung; Woo, Chang Gok; Lee, Saet-Byeol; Chin, Susie; Kim, Hee Kyung; Kwak, Jeong Ja; Koh, Eun Suk; Lee, Bora; Moon, Ahrim

doi:10.1016/j.pathol.2017.06.001

Cited by 15 publications

(19 citation statements)

References 19 publications

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“…EGFR function is frequently altered in cancer (Santarius et al, 2010;Yarden and Pines, 2012). Excessive protein levels due to gene amplification or increasedtranscription are the most common EGFR perturbations found in gastrointestinal and lung adenocarcinoma as well as in cholangiocarcinoma (Birkman et al, 2016;Jung et al, 2017;Li et al, 2008). On the other hand, EGFR kinase domain activating point mutations are associated with non-small cell lung carcinoma and glioblastoma, but are rarely seen in other types of cancer (Li et al, 2008;Siegelin and Borczuk, 2014;Zhang et al, 2016).…”

Section: Ral Gtpases As Potential Therapeutic Targets In Cancermentioning

confidence: 99%

RAL GTPases mediate EGFR-driven intestinal stem cell hyperproliferation and tumourigenesis

Nászai

Bellec

et al. 2020

Preprint

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SummaryRAS-like (RAL) GTPases function in Wnt signalling-dependent intestinal stem cell proliferation and regeneration. Whether RAL proteins work as canonical RAS effectors in the intestine, and the mechanisms of how they contribute to tumorigenesis remain unclear. Here, we show that RAL GTPases are necessary and sufficient to activate EGFR/MAPK signalling in the intestine. We identify non-canonical roles of RAL GTPases, not as RAS effectors, but rather by acting upstream of RAS activation via induction of EGFR internalization. Knocking down Drosophila RalA from intestinal stem and progenitor cells leads to increased levels of plasma membrane-associated EGFR and decreased MAPK pathway activation. Importantly, in addition to impacting stem cell proliferation and damage-induced intestinal regeneration, this function of RAL GTPases drives EGFR-dependent tumorigenic growth in the intestine and in human mammary epithelium. Altogether, our results reveal previously unrecognised cellular and molecular contexts where RAL GTPases become essential mediators of EGFR-driven tissue homeostasis and malignant growth.

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Section: Ral Gtpases As Potential Therapeutic Targets In Cancermentioning

confidence: 99%

RAL GTPases mediate EGFR-driven intestinal stem cell hyperproliferation and tumourigenesis

Nászai

Bellec

et al. 2020

Preprint

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“…27 In another study, the researchers studied HER2/neu expression in extrahepatic CCA patients ( n = 84) and reported that anticancer therapy targeting HER2 receptors may be a reasonable option for these patients. 28 Our patient has responded very well to anti-HER2 drugs and showed an improvement in symptoms, lab results and shrinkage in tumor size. This implicates the use of targeted therapy as a favorable option in CCA alongside other patients who received anti-HER2-based therapy (Table 2).…”

Section: Discussionmentioning

confidence: 59%

“…19 cases were positive per IHC (10 were scored as +2 and one as +3)No treatment data provided–Sorscher et al 30 2013Gallbladder cancer—1 patient HER2/neu+++Trastuzumab + weekly paclitaxel (chemo later discontinued)Marked partial response (5.4 cm → 1.3 cm). Duration of response ongoing (at least 6 months)Jung et al 28 20173/84 patients with HER2/neu+ distal extrahepatic CC (3.6%)No treatment data provided–Yoshikawa et al 21 2007HER2/neu expression 0.9% in intrahepatic CC and 8.5% in extrahepatic CCNo treatment data provided–…”

Section: Discussionmentioning

confidence: 99%

Trastuzumab and pertuzumab in circulating tumor DNA ERBB2-amplified HER2-positive refractory cholangiocarcinoma

et al. 2019

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Cholangiocarcinoma is a heterogeneous and target-rich disease with differences in actionable targets. Intrahepatic and extrahepatic types of cholangiocarcinoma differ significantly in clinical presentation and underlying genetic aberrations. Research has shown that extrahepatic cholangiocarcinoma is more likely to be associated with ERBB2 (HER2) genetic aberrations. Various anti-HER2 clinical trials, case reports and other molecular studies show that HER2 is a real target in cholangiocarcinoma; however, anti-HER2 agents are still not approved for routine administration. Here, we show in a metastatic cholangiocarcinoma with ERBB2 amplification identified on liquid biopsy (circulating tumor DNA (ctDNA) testing), a dramatic response to now over 12 months of dual-anti-HER2 therapy. We also summarize the current literature on anti-HER2 therapy for cholangiocarcinoma. This would likely become another treatment option for this target-rich disease.

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“…EGFR transactivation in cancer cells can confer properties, such as growth, survival, and angiogenesis to cancer cells [ 5 ]. Previously,a study revealed that both EGFR expression and gene copy number variations are associated with poor prognosis of cancers [ 6 ]. The expression level of the downstream signal of the ErbB 2-mediated signaling pathway indicates that overexpression of the ErbB2 receptor leads to actin cytoskeleton remodeling, alterations in cell adhesion, and increased exercise capacity and invasiveness, leading to the transfer and escape of anti-tumor immunity [ 7 ].…”

Section: Introductionmentioning

confidence: 99%

First-in-human, phase I single-ascending-dose study of the safety, pharmacokinetics, and relative bioavailability of selatinib, a dual EGFR-ErbB2 inhibitor in healthy subjects

et al. 2020

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Summary We assessed the pharmacokinetics and safety of a single oral administration of selatinib to healthy Chinese subjects and evaluated the potential bioavailability advantage of selatinib relative to lapatinib. Healthy subjects aged 18–40 years were enrolled in this two-part study: Part 1, a single ascending dose (50–500 mg), randomized, double-blind, placebo-control study with 64 subjects; and Part 2, an open-label, positive control, randomized, three-treatment, three-period, three-sequence crossover design study, with 6 subjects administered a single 500-mg dose of selatinib tablets (A), selatinib suspension (B), or lapatinib tablets C) per cycle. In part 1, selatinib was well-tolerated up to the planned maximum dose of 500 mg; thus the maximum tolerated dose was not attained. Twenty-two adverse events were observed in 19 (36.5%) of the 52 subjects administered the test drug. The most common drug-related adverse event was diarrhea. The mean selatinib peak plasma concentration was 69.4–494 ng/mL, which was achieved in a median peak time of 3.5–4.5 h, with a mean elimination half-life between 13.8 and 15.8 h. In Part 2, A and B showed similar bioavailability. Plasma exposure to the active drug (selatinib plus the metabolite, lapatinib) after A intake was more than two-fold higher than that of the same dose of C. In the dose range of 50–500 mg, selatinib was safe and well-tolerated by healthy Chinese subjects, and it conformed with linear pharmacokinetics. Active exposure to selatinib was much greater than that to lapatinib, supporting its development as an adjuvant for anticancer treatment.

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Gene copy number variation and protein overexpression of EGFR and HER2 in distal extrahepatic cholangiocarcinoma

Cited by 15 publications

References 19 publications

RAL GTPases mediate EGFR-driven intestinal stem cell hyperproliferation and tumourigenesis

RAL GTPases mediate EGFR-driven intestinal stem cell hyperproliferation and tumourigenesis

Trastuzumab and pertuzumab in circulating tumor DNA ERBB2-amplified HER2-positive refractory cholangiocarcinoma

First-in-human, phase I single-ascending-dose study of the safety, pharmacokinetics, and relative bioavailability of selatinib, a dual EGFR-ErbB2 inhibitor in healthy subjects

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