Deficient HER3 expression in poorly-differentiated colorectal cancer cells enhances gefitinib sensitivity

Nakata, Susumu; Tanaka, Harunari; Ito, Y.; Hara, Masayasu; Fujita, Mitsugu; Kondo, Eisaku; Kanemitsu, Yukihide; Yatabe, Yasushi; Nakanishi, Hayao

doi:10.3892/ijo.2014.2538

Cited by 14 publications

(13 citation statements)

References 35 publications

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“…This might be applicable for CRC, also a solid tumor dependent on the HER axis [23]. Nakata et al suggests that HER3 deficiency, EGFR/ HER2 proficiency and poor differentiation enhance the gefitinib effect in CRC cells [24]. Gala et al shows that when resistance to chemotherapy (5-FU + irinotecan) occurs, a patient with HER3 expression in breast cancer can benefit from cetuximab treatment [25].…”

Section: Discussionmentioning

confidence: 99%

HER3 expression is correlated to distally located and low-grade colon cancer

et al. 2016

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Background HER3 is a member of the human epidermal growth factor receptor complex (EGFR, HER2, HER3 and HER4). It has been investigated as a prognostic biomarker in colorectal cancer but is sparingly studied in colon cancer. HER3 can affect cellular proliferation, differentiation and migration in oncogenesis through ligand binding and activation of intracellular signal pathways. Recently, we found that expression of cell surface HER3 can be detected at a high extent in primary colorectal tumors, lymph node and liver metastases and that it correlated with poor prognosis. This large, explorative, retrospective study evaluates the prognostic value of HER3 in colon cancer and the association of HER3 to tumor location. Material and methods. Immunohistochemical detection with a monoclonal HER3 antibody in primary colon tumors of stage II and III, from 521 patients, was performed. Results HER3 was expressed at high levels in 67% of the colon tumors. High HER3 expression was associated with distal tumor location (p50.0001) and low-grade tumor (p50.0001). In the group of patients with distal colon cancer (230/521), HER3 expression correlated to shorter disease-free survival (DFS) (p ¼ 0.03) in the univariate analysis and in the multivariate analysis, a hazard ratio of 0.56 (95% CI 0.31-0.99) (p ¼ 0.047) was observed. Conclusion In this explorative, retrospective study, high HER3 expression in colon cancer was associated to distal colon location and low-grade tumor. High HER3 expression was of prognostic value according to DFS in distal colon cancer in univariate and multivariate analysis. We could not find a significant value of HER3 expression with respect to overall survival (OS).

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Section: Discussionmentioning

confidence: 99%

HER3 expression is correlated to distally located and low-grade colon cancer

et al. 2016

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“…However, researchers have found that a heregulin–EGFR–HER3 autocrine signaling axis mediated acquired lapatinib resistance in HER2 + breast cancer models which no longer depended on HER2–HER3–PI3K signal pathway 20 . What׳s more, overexpression of HER3 in COLM-5 cells can lead to significant resistance to gefitinib in vitro and in vivo 21 . All of these studies highlight the central role of HER3 in cancers.…”

Section: The Aberrated Activation Of the Bypass Pathways Induce Resismentioning

confidence: 99%

Mechanisms of resistance to EGFR tyrosine kinase inhibitors

2015

Acta Pharmaceutica Sinica B

413

362

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Since the discovery that non-small cell lung cancer (NSCLC) is driven by epidermal growth factor receptor (EGFR) mutations, the EGFR tyrosine kinase inhibitors (EGFR-TKIs, e.g., gefitinib and elrotinib) have been effectively used for clinical treatment. However, patients eventually develop drug resistance. Resistance to EGFR-TKIs is inevitable due to various mechanisms, such as the secondary mutation (T790M), activation of alternative pathways (c-Met, HGF, AXL), aberrance of the downstream pathways (K-RAS mutations, loss of PTEN), impairment of the EGFR-TKIs-mediated apoptosis pathway (BCL2-like 11/BIM deletion polymorphism), histologic transformation, ATP binding cassette (ABC) transporter effusion, etc. Here we review and summarize the known resistant mechanisms to EGFR-TKIs and provide potential targets for development of new therapeutic strategies.

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“…Jacobsen et al [ 31 ] and Li et al [ 32 ] have found that the expression of Her3 increased in breast cancer resistant cell lines (MDA-MB-175-VII) and ovarian cancer drug-resistant cell lines (SKOV3-T) after trastuzumab treatment. Nakata et al [ 33 ] reported that increased Her3 expression increased gefitinib resistance in patients with poorly differentiated CRC. Data from patients with KRAS wild-type mCRC in the GALGB/SWOG 80405 clinical trials revealed that patients with the primary tumor site of mCRC in the left colon could benefit from cetuximab.…”

Section: Discussionmentioning

confidence: 99%

Association between the overexpression of Her3 and clinical pathology and prognosis of colorectal cancer

et al. 2018

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Background:This study aimed to investigate the association between the overexpression of human epidermal growth factor receptor-3 (Her3) and the clinicopathological parameters and survival of patients with colorectal cancer (CRC).Methods:Relevant studies on the overexpression of Her3 (measured by immunohistochemistry) and overall survival (OS) in patients with CRC were searched for in PubMed, EMBASE, and Cochrane Library. Published data were extracted and computed into odds ratios (ORs) for assessing the association of Her3 overexpression with tumor differentiation, tumor node metastasis (TNM) stage, position of colon cancer, sex, and age. Prognostic data were computed into hazard ratios (HRs) for OS.Results:Eight studies including 1716 patients with CRC were included in this meta-analysis. The results revealed a significant association between Her3 overexpression and tumor differentiation [OR = 2.38; 95% confidence interval (95% CI): 1.76–3.22; P < .001], TNM tumor stage (OR = 0.71; 95% CI: 0.53–0.96; P = .03), and position of colon cancer (OR = 1.71; 95% CI: 1.28–2.27; P < .001). While patients with Her3 overexpression demonstrated a worse tumor response (OR = 0.31; 95% CI: 0.16–0.60; P < .001) and OS after treatment with cetuximab (HR = 1.86; 95% CI: 1.24–2.79; P = .003), they demonstrated better OS after symptomatic treatment (HR = 0.65; 95% CI: 0.50–0.85; P = .002). Her3 overexpression was not associated with sex (OR = 1.03; 95% CI: 0.83–1.28; P = .79), age (OR = 0.96; 95% CI: 0.75–1.24; P = .77), colon or rectum site (OR = 0.79; 95% CI: 0.44–1.43; P = .44), and total OS (HR = 1.09; 95% CI: 0.69–1.72; P = .72).Conclusion:Her3 expression is associated with the clinical pathology and prognosis of CRC, which explains the nonefficacy of cetuximab treatment in patients with CRC.

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Deficient HER3 expression in poorly-differentiated colorectal cancer cells enhances gefitinib sensitivity

Cited by 14 publications

References 35 publications

HER3 expression is correlated to distally located and low-grade colon cancer

HER3 expression is correlated to distally located and low-grade colon cancer

Mechanisms of resistance to EGFR tyrosine kinase inhibitors

Association between the overexpression of Her3 and clinical pathology and prognosis of colorectal cancer

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