{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,24]],"date-time":"2026-07-24T17:24:38Z","timestamp":1784913878050,"version":"3.55.0"},"reference-count":56,"publisher":"Wiley","issue":"8","license":[{"start":{"date-parts":[[2018,12,8]],"date-time":"2018-12-08T00:00:00Z","timestamp":1544227200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100009053","name":"DBT India Alliance","doi-asserted-by":"publisher","award":["IA\/I\/11\/2500278"],"award-info":[{"award-number":["IA\/I\/11\/2500278"]}],"id":[{"id":"10.13039\/501100009053","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Intl Journal of Cancer"],"published-print":{"date-parts":[[2019,4,15]]},"abstract":"<jats:p>\n                    The uncommonness of gallbladder cancer in the developed world has contributed to the generally poor understanding of the disease. Our integrated analysis of whole exome sequencing, copy number alterations, immunohistochemical, and phospho\u2010proteome array profiling indicates\n                    <jats:italic>ERBB2<\/jats:italic>\n                    alterations in 40% early\u2010stage rare gallbladder tumors, among an ethnically distinct population not studied before, that occurs through overexpression in 24% (\n                    <jats:italic>n<\/jats:italic>\n                    = 25) and recurrent mutations in 14% tumors (\n                    <jats:italic>n<\/jats:italic>\n                    = 44); along with co\u2010occurring\n                    <jats:italic>KRAS<\/jats:italic>\n                    mutation in 7% tumors (\n                    <jats:italic>n<\/jats:italic>\n                    = 44). We demonstrate that ERBB2 heterodimerizes with EGFR to constitutively activate the ErbB signaling pathway in gallbladder cells. Consistent with this, treatment with\n                    <jats:italic>ERBB2<\/jats:italic>\n                    \u2010specific,\n                    <jats:italic>EGFR<\/jats:italic>\n                    \u2010specific shRNA or with a covalent EGFR family inhibitor Afatinib inhibits tumor\u2010associated characteristics of the gallbladder cancer cells. Furthermore, we observe an\n                    <jats:italic>in vivo<\/jats:italic>\n                    reduction in tumor size of gallbladder xenografts in response to Afatinib is paralleled by a reduction in the amounts of phospho\u2010ERK, in tumors harboring\n                    <jats:italic>KRAS<\/jats:italic>\n                    (G13D) mutation but not in\n                    <jats:italic>KRAS<\/jats:italic>\n                    (G12V) mutation, supporting an essential role of the ErbB pathway. In overall, besides implicating\n                    <jats:italic>ERBB2<\/jats:italic>\n                    as an important therapeutic target under neo\u2010adjuvant or adjuvant settings, we present the first evidence that the presence of\n                    <jats:italic>KRAS<\/jats:italic>\n                    mutations may preclude gallbladder cancer patients to respond to anti\u2010EGFR treatment, similar to a clinical algorithm commonly practiced to opt for anti\u2010EGFR treatment in colorectal cancer.\n                  <\/jats:p>","DOI":"10.1002\/ijc.31916","type":"journal-article","created":{"date-parts":[[2018,10,10]],"date-time":"2018-10-10T15:55:06Z","timestamp":1539186906000},"page":"2008-2019","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":48,"title":["ERBB2 and KRAS alterations mediate response to EGFR inhibitors in early stage gallbladder cancer"],"prefix":"10.1002","volume":"144","author":[{"given":"Prajish","family":"Iyer","sequence":"first","affiliation":[{"name":"Integrated Cancer Genomics Laboratory Advanced Centre for Treatment Research Education in Cancer (ACTREC), Tata Memorial Centre  Navi Mumbai Maharashtra India"},{"name":"Homi Bhabha National Institute  Mumbai Maharashtra India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shailesh V.","family":"Shrikhande","sequence":"additional","affiliation":[{"name":"Homi Bhabha National Institute  Mumbai Maharashtra India"},{"name":"Department of Gastrointestinal and Hepato\u2010Pancreato\u2010Biliary Surgical Oncology Tata Memorial Centre, Ernest Borges Marg  Mumbai Maharashtra India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Malika","family":"Ranjan","sequence":"additional","affiliation":[{"name":"Integrated Cancer Genomics Laboratory Advanced Centre for Treatment Research Education in Cancer (ACTREC), Tata Memorial Centre  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