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|Ref Type||Journal Article|
|Authors||Le Joncour V, Martins A, Puhka M, Isola J, Salmikangas M, Laakkonen P, Joensuu H, Barok M|
|Title||A Novel Anti-HER2 Antibody-Drug Conjugate XMT-1522 for HER2-Positive Breast and Gastric Cancers Resistant to Trastuzumab Emtansine.|
|Journal||Molecular cancer therapeutics|
|Abstract Text||Most patients with HER2-positive breast or gastric cancer exhibit primary or acquired resistance to trastuzumab emtansine (T-DM1), and such patients may have limited therapeutic options. XMT-1522 is a novel anti-HER2 antibody-drug conjugate. We compared XMT-1522 to T-DM1 in preclinical models. The effects of XMT-1522 and T-DM1 on cell survival and apoptosis were compared in six HER2-positive breast cancer or gastric cancer cell lines, of which three lines were T-DM1-sensitive (N-87, OE-19, JIMT-1) and three T-DM1-resistant (RN-87, ROE-19, SNU-216). We compared these agents also in the HER2-negative breast cancer cell line MCF-7, and in mouse RN-87 and JIMT-1 xenograft models. Cell survival was assessed using the AlamarBlue method and apoptosis with the Caspase-Glo 3/7 method. XMT-1522 inhibited the growth of all six HER2-positive cell lines. The proportions of cells that survived XMT-1522 treatment were smaller as compared with T-DM1, particularly in the T-DM1-resistant cell lines. XMT-1522 induced more cell apoptosis compared with T-DM1. While RN-87 and JIMT-1 xenograft tumors progressed on T-DM1 treatment, all tumors responded to XMT-1522, and all but one tumor disappeared during the XMT-1522 treatment. XMT-1522 had a strong antitumor effect on RN-87 and JIMT-1 xenografts that progressed on T-DM1. We conclude that XMT-1522 was effective in HER2-positive breast cancer and gastric cancer cell lines resistant to T-DM1, and in xenograft models resistant to T-DM1. The results support the testing of XMT-1522 in clinical trials in patients with HER2-positive cancer.|
|Molecular Profile||Treatment Approach|
|Gene Name||Source||Synonyms||Protein Domains||Gene Description||Gene Role|
|Therapy Name||Drugs||Efficacy Evidence||Clinical Trials|
|Drug Name||Trade Name||Synonyms||Drug Classes||Drug Description|
|XMT-1522||HER2 (ERBB2) Antibody 47||XMT-1522 is an antibody-drug conjugate comprising an ERBB2 (HER2)-targeted antibody linked to auristatin, which delivers the cytotoxic agent to Erbb2 (Her2)-expressing tumor cells, potentially resulting in decreased tumor growth (PMID: 31292166).|
|Gene||Variant||Impact||Protein Effect||Variant Description||Associated with drug Resistance|
|Molecular Profile||Indication/Tumor Type||Response Type||Therapy Name||Approval Status||Evidence Type||Efficacy Evidence||References|
|ERBB2 positive||breast cancer||sensitive||XMT-1522||Preclinical - Cell line xenograft||Actionable||In a preclinical study, XMT-1522 demonstrated improved efficacy compared to Kadcyla (ado-trastuzumab emtansine), inhibited growth of Erbb2 (Her2)-positive breast cancer cells in culture, resulted in tumor regression and prolonged survival in cell line xenograft models (PMID: 31292166).||31292166|
|ERBB2 positive||stomach cancer||sensitive||XMT-1522||Preclinical - Cell line xenograft||Actionable||In a preclinical study, XMT-1522 demonstrated improved efficacy compared to Kadcyla (ado-trastuzumab emtansine), inhibited growth of Erbb2 (Her2)-positive gastric cancer cell lines in culture, resulted in tumor regression and prolonged survival in cell line xenograft models (PMID: 31292166).||31292166|