Dual HER2 inhibition strategies in the management of treatment-refractory metastatic colorectal cancer: History and status

Kanat, Özkan; Ertas, Hulya; Caner, Burcu

doi:10.12998/wjcc.v6.i11.418

Cited by 9 publications

(8 citation statements)

References 48 publications

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“…A number of studies revealed the presence of HER2 amplification and/or activation by overexpression of the HER3/4 ligand, heregulin, in CRC patient samples or patient-derived xenograft models with acquired resistance to anti-EGFR treatment [36,37,38,48]. Among the EGFR family, HER2 is the one with the strongest catalytic activity and it usually dimerizes with EGFR (HER1) and HER3 [17].…”

Section: Acquired Resistance To Anti-egfr Treatment In Crc Patientsmentioning

confidence: 99%

Immune Resistance and EGFR Antagonists in Colorectal Cancer

Giordano

Remo²,

Porrás

et al. 2019

Cancers

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: Targeting the epidermal growth factor receptor (EGFR) either alone or in combination with chemotherapy in patients with RAS wild type metastatic colorectal cancer (mCRC) has revolutionized the treatment of CRC, but with less results than initially envisaged. In recent years, the discovery of multiple pathways leading to the escape from anti-EGFR therapy has revealed an enormous complexity and heterogeneity of human CRC due to the intrinsic genomic instability and immune/cancer cell interaction. Therefore, understanding the mechanistic basis of acquired resistance to targeted therapies represents a major challenge to improve the clinical outcomes of patients with CRC. The latest findings strongly suggest that complex molecular alterations coupled with changes of the immune tumor microenvironment may substantially contribute to the clinical efficacy of EGFR antagonist. In this review, we discuss the most recent findings that contribute to both primary and acquired anti-EGFR therapy resistance. In addition, we analyze how strategies aiming to enhance the favorable effects in the tumor microenvironment may contribute to overcome resistance to EGFR therapies.

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Section: Acquired Resistance To Anti-egfr Treatment In Crc Patientsmentioning

confidence: 99%

Immune Resistance and EGFR Antagonists in Colorectal Cancer

Giordano

Remo²,

Porrás

et al. 2019

Cancers

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“…In the past two decades, systemic chemotherapy b one of the foremost choices for advanced CRC treatment 36. Recently, molecule-targeted agents, such as cetuximab,37 panitumumab,38,39 bevacizumab,40 regorafenib41,42 and ramucirumab,43,44 that inhibit RTKs activation have been approved for use in CRC treatment. Downregulation of RTKs’ activity can attenuate tumor cell growth, metastasis, and angiogenesis 45–47.…”

Section: Discussionmentioning

confidence: 99%

<p>MicroRNA-940 restricts the expression of metastasis-associated gene MACC1 and enhances the antitumor effect of Anlotinib on colorectal cancer</p>

Wang¹,

Zhao²,

Zhao³

et al. 2019

OTT

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Background: Metastasis-associated with colon cancer-1 (MACC1) is an important regulator that promotes colorectal cancer (CRC) cells’ proliferation and distant metastasis. Therefore, MACC1 is considered as a promising therapeutic target of CRC. This work aimed to identify the microRNA (miR) targeted to MACC1, and to study the potential of using the particular miR in enhancing the antitumor effect of chemotherapy. Materials and methods: miR prediction was performed in the miR database. The effect of miR-940 on MACC1’s expression was examined by Western blot, and the effect of miR-940 on the expression of genes related to the epithelial–mesenchymal transition (EMT) was identified by quantitative real-time polymerase chain reaction experiments. In vivo growth of CRC cells were analyzed in the nude mice subcutaneous tumor model and CRC liver metastasis model. Results: By using the database, miR-940 was identified to target to the 3ʹUTR of MACC1’s mRNA. Experimentally, transfection of miR-940 decreased the expression of MACC1 in CRC cells and inhibited the EMT process of the transfected cells. MiR-940 also enhanced the inhibitory effect of Anlotinib on CRC cells’ in vivo growth and invasion. Correspondingly, ectopic expression of MACC1 mutant, which does not contain miR-940 binding site, blocked the antitumor effect of miR-940 on CRC cells. Conclusion: MiR-940 restricts the proliferation and invasion of CRC cells by targeting to MACC1’s mRNA, and enhances the antitumor effect of Anlotinib on CRC tumors.

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“…Recently, molecular-targeted agents [17], such as cetuximab and panizumab [18], bevacizumab [19,20], regofenib [21] , remoluzumab [22,23] and RTKs [24,25] have been used clinically in the treatment of CRC. However, little research has been done on multidrug-resistant cells in colorectal cancer.…”

Section: Discussionmentioning

confidence: 99%

Anlotinib overcomes multiple drug resistant of the colorectal cancer cells via inactivating PI3K/AKT pathway

Lan

Zhao

Shang

et al. 2019

Preprint

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Background: Anlotinib is a multi-tyrosine kinase inhibitor that has been reported to have activity against colorectal cancer. However, the functional mechanisms whereby anlotinib mediates against deadly drug-resistant colorectal cancer (CRC) has not been fully describedspecifically, the potential mechanisms that inhibit proliferation and induce apoptosis remain largely unknown. Methods:MTT assays were used to detect cell viability and calculate the resistance index. Colony formation was used to evaluate the proliferation of resistant cells. DAPI staining was used to detect cell apoptosis morphologically. Annexin V-FITC with PI staining was used to detect early and late-stage apoptosis of cells. Cell cycle distribution was determined by Flow cytometry. Transwell assays were performed to examine the ability of migration and invasion. Cyclin D1 Survivin, CDK4, Bcl-2, Bax and changes of PI3K/AKT pathway were detected by Western blotting. Compared as a single agent or combined with anlotinib or LY294002, PI3K inhibitor (LY294002) was used to verify whether it inhibited drug-resistant CRC cells by lowering PI3K/AKT. Results: HCT-8/5-FU cells showed multiple drug resistance. Drug resistance index of 5-FU, ADM and DDP were 390.27, 2.55 and 4.57, respectively. Anlotinib was shown to inhibit cell viability on HCT-8/5-FU and HCT-8 cells for 24 h and 48 h in a dosage-and time-dependent pattern. Compared with 48 h, intervened with anlotinib (0 μM, 10 μM, 20 μM and 40 μM) for 24 h, the HCT-8/5-FU cells were sensitive to anlotinib, and their sensitivity was greater than that of the parent cell line (HCT-8) at 24 h. Further, anlotinib inhibited the number of cloned cells significantly and had a significant inhibitory effect on cell cycle, mainly by blocking G1 transferring to S phase. Moreover, anlotinib could down-regulate the expression of survivin, cyclin D1, CDK4, caspase-3, Bcl-2, MMP-2, vimentin, MMP-9, and N-cadherin, while up-regulating cleaved-caspase-3, Bax and E-cadherin. Anlotinib inhibited the activity of the PI3K/AKT pathway and induced apoptosis in HCT-8/5-FU cells. Using LY294002, a specific PI3K inhibitor, our experiment found anlotinib can inhibit drug-resistant CRC cells by reducing PI3K and p-AKT activity-induce apoptosis.Conclusions: Anlotinib inhibited the proliferation , metastasis and induced apoptosis of HCT-8 / 5-FU cells ; and the mechanism could be that anlotinib overcomes multiple drug resistant of the colorectal cancer cells via inactivating PI3K/AKT pathway .

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Dual HER2 inhibition strategies in the management of treatment-refractory metastatic colorectal cancer: History and status

Cited by 9 publications

References 48 publications

Immune Resistance and EGFR Antagonists in Colorectal Cancer

Immune Resistance and EGFR Antagonists in Colorectal Cancer

<p>MicroRNA-940 restricts the expression of metastasis-associated gene MACC1 and enhances the antitumor effect of Anlotinib on colorectal cancer</p>

Anlotinib overcomes multiple drug resistant of the colorectal cancer cells via inactivating PI3K/AKT pathway

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