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ERBB2 and KRAS alterations mediate response to EGFR inhibitors in early stage gallbladder cancer
Author(s) -
Iyer Prajish,
Shrikhande Shailesh V.,
Ranjan Malika,
Joshi Asim,
Gardi Nilesh,
Prasad Ratnam,
Dharavath Bhasker,
Thorat Rahul,
Salunkhe Sameer,
Sahoo Bikram,
Chandrani Pratik,
Kore Hitesh,
Mohanty Bhabani,
Chaudhari Vikram,
Choughule Anuradha,
Kawle Dhananjay,
Chaudhari Pradip,
Ingle Arvind,
Banavali Shripad,
Gera Poonam,
Ramadwar Mukta R.,
Prabhash Kumar,
Barreto Savio George,
Dutt Shilpee,
Dutt Amit
Publication year - 2018
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.31916
Subject(s) - kras , afatinib , gallbladder cancer , cancer research , gallbladder , epidermal growth factor receptor , egfr inhibitors , biology , cancer , population , erbb , colorectal cancer , medicine , cetuximab , pathology , erlotinib , environmental health
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.