ERBB2 and KRAS alterations mediate response to EGFR inhibitors in early stage gallbladder cancer.

Autor: Iyer P; Integrated Cancer Genomics Laboratory, Advanced Centre for Treatment Research Education in Cancer (ACTREC), Tata Memorial Centre, Navi Mumbai, Maharashtra, India.; Homi Bhabha National Institute, Mumbai, Maharashtra, India., Shrikhande SV; Homi Bhabha National Institute, Mumbai, Maharashtra, India.; Department of Gastrointestinal and Hepato-Pancreato-Biliary Surgical Oncology, Tata Memorial Centre, Ernest Borges Marg, Mumbai, Maharashtra, India., Ranjan M; Integrated Cancer Genomics Laboratory, Advanced Centre for Treatment Research Education in Cancer (ACTREC), Tata Memorial Centre, Navi Mumbai, Maharashtra, India., Joshi A; Integrated Cancer Genomics Laboratory, Advanced Centre for Treatment Research Education in Cancer (ACTREC), Tata Memorial Centre, Navi Mumbai, Maharashtra, India.; Homi Bhabha National Institute, Mumbai, Maharashtra, India., Gardi N; Integrated Cancer Genomics Laboratory, Advanced Centre for Treatment Research Education in Cancer (ACTREC), Tata Memorial Centre, Navi Mumbai, Maharashtra, India., Prasad R; Integrated Cancer Genomics Laboratory, Advanced Centre for Treatment Research Education in Cancer (ACTREC), Tata Memorial Centre, Navi Mumbai, Maharashtra, India., Dharavath B; Integrated Cancer Genomics Laboratory, Advanced Centre for Treatment Research Education in Cancer (ACTREC), Tata Memorial Centre, Navi Mumbai, Maharashtra, India.; Homi Bhabha National Institute, Mumbai, Maharashtra, India., Thorat R; Laboratory Animal Facility, Advanced Centre for Treatment, Research and Education in Cancer, Tata Memorial Centre, Navi Mumbai, Maharashtra, India., Salunkhe S; Homi Bhabha National Institute, Mumbai, Maharashtra, India.; Shilpee laboratory, Advanced Centre for Treatment Research Education In Cancer (ACTREC), Tata Memorial Centre, Navi Mumbai, Maharashtra, India., Sahoo B; Integrated Cancer Genomics Laboratory, Advanced Centre for Treatment Research Education in Cancer (ACTREC), Tata Memorial Centre, Navi Mumbai, Maharashtra, India., Chandrani P; Integrated Cancer Genomics Laboratory, Advanced Centre for Treatment Research Education in Cancer (ACTREC), Tata Memorial Centre, Navi Mumbai, Maharashtra, India., Kore H; Integrated Cancer Genomics Laboratory, Advanced Centre for Treatment Research Education in Cancer (ACTREC), Tata Memorial Centre, Navi Mumbai, Maharashtra, India., Mohanty B; Small Animal Imaging facility, Advanced Centre for Treatment Research Education In Cancer (ACTREC), Tata Memorial Centre, Navi Mumbai, Maharashtra, India., Chaudhari V; Department of Gastrointestinal and Hepato-Pancreato-Biliary Surgical Oncology, Tata Memorial Centre, Ernest Borges Marg, Mumbai, Maharashtra, India., Choughule A; Department of Medical Oncology, Tata Memorial Centre, Ernest Borges Marg, Mumbai, Maharashtra, India., Kawle D; Integrated Cancer Genomics Laboratory, Advanced Centre for Treatment Research Education in Cancer (ACTREC), Tata Memorial Centre, Navi Mumbai, Maharashtra, India., Chaudhari P; Small Animal Imaging facility, Advanced Centre for Treatment Research Education In Cancer (ACTREC), Tata Memorial Centre, Navi Mumbai, Maharashtra, India., Ingle A; Laboratory Animal Facility, Advanced Centre for Treatment, Research and Education in Cancer, Tata Memorial Centre, Navi Mumbai, Maharashtra, India., Banavali S; Homi Bhabha National Institute, Mumbai, Maharashtra, India.; Department of Medical Oncology, Tata Memorial Centre, Ernest Borges Marg, Mumbai, Maharashtra, India., Gera P; Tissue Biorepository, Advanced Centre for Treatment Research and Education in Cancer (ACTREC), Tata Memorial Centre, Navi Mumbai, Maharashtra, India., Ramadwar MR; Homi Bhabha National Institute, Mumbai, Maharashtra, India.; Department of Pathology, Tata Memorial Centre, Ernest Borges Marg, Mumbai, Maharashtra, India., Prabhash K; Homi Bhabha National Institute, Mumbai, Maharashtra, India.; Department of Medical Oncology, Tata Memorial Centre, Ernest Borges Marg, Mumbai, Maharashtra, India., Barreto SG; Department of Gastrointestinal and Hepato-Pancreato-Biliary Surgical Oncology, Tata Memorial Centre, Ernest Borges Marg, Mumbai, Maharashtra, India., Dutt S; Homi Bhabha National Institute, Mumbai, Maharashtra, India.; Shilpee laboratory, Advanced Centre for Treatment Research Education In Cancer (ACTREC), Tata Memorial Centre, Navi Mumbai, Maharashtra, India., Dutt A; Integrated Cancer Genomics Laboratory, Advanced Centre for Treatment Research Education in Cancer (ACTREC), Tata Memorial Centre, Navi Mumbai, Maharashtra, India.; Homi Bhabha National Institute, Mumbai, Maharashtra, India.
Jazyk: angličtina
Zdroj: International journal of cancer [Int J Cancer] 2019 Apr 15; Vol. 144 (8), pp. 2008-2019. Date of Electronic Publication: 2018 Dec 08.
DOI: 10.1002/ijc.31916
Abstrakt: 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-proteome array profiling indicates ERBB2 alterations in 40% early-stage rare gallbladder tumors, among an ethnically distinct population not studied before, that occurs through overexpression in 24% (n = 25) and recurrent mutations in 14% tumors (n = 44); along with co-occurring KRAS mutation in 7% tumors (n = 44). We demonstrate that ERBB2 heterodimerizes with EGFR to constitutively activate the ErbB signaling pathway in gallbladder cells. Consistent with this, treatment with ERBB2-specific, EGFR-specific shRNA or with a covalent EGFR family inhibitor Afatinib inhibits tumor-associated characteristics of the gallbladder cancer cells. Furthermore, we observe an in vivo reduction in tumor size of gallbladder xenografts in response to Afatinib is paralleled by a reduction in the amounts of phospho-ERK, in tumors harboring KRAS (G13D) mutation but not in KRAS (G12V) mutation, supporting an essential role of the ErbB pathway. In overall, besides implicating ERBB2 as an important therapeutic target under neo-adjuvant or adjuvant settings, we present the first evidence that the presence of KRAS mutations may preclude gallbladder cancer patients to respond to anti-EGFR treatment, similar to a clinical algorithm commonly practiced to opt for anti-EGFR treatment in colorectal cancer.
(© 2018 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)
Databáze: MEDLINE
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