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

Abstract

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.

• Authors: Prajish Iyer, Shailesh V Shrikhande, Malika Ranjan, Asim Joshi, Nilesh Gardi, Ratnam Prasad, Bhasker Dharavath, Rahul Thorat, Sameer Salunkhe, Bikram Sahoo, Pratik Chandrani, Hitesh Kore, Bhabani Mohanty, Vikram Chaudhari, Anuradha Choughule, Dhananjay Kawle, Pradip Chaudhari, Arvind Ingle, Shripad Banavali, Poonam Gera, Mukta R Ramadwar, Kumar Prabhash, Savio George Barreto, Shilpee Dutt, Amit Dutt
• Journal: International journal of cancer (Int J Cancer) Vol. 144 Issue 8 Pg. 2008-2019 (04 15 2019) ISSN: 1097-0215 [Electronic] United States
• PMID: 30304546 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2018 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.

Chemical References

• Antineoplastic Agents
• KRAS protein, human
• Afatinib
• EGFR protein, human
• ERBB2 protein, human
• ErbB Receptors
• Receptor, ErbB-2
• Proto-Oncogene Proteins p21(ras)

Topics

• Adult
• Afatinib (pharmacology, therapeutic use)
• Aged
• Animals
• Antineoplastic Agents (pharmacology, therapeutic use)
• Cell Line, Tumor
• DNA Mutational Analysis
• ErbB Receptors (antagonists & inhibitors, metabolism)
• Female
• Gallbladder (pathology)
• Gallbladder Neoplasms (drug therapy, genetics, pathology)
• Humans
• Male
• Mice
• Mice, Inbred NOD
• Mice, SCID
• Middle Aged
• Mutation
• Neoplasm Staging
• Phosphorylation (drug effects)
• Proto-Oncogene Proteins p21(ras) (genetics)
• Receptor, ErbB-2 (genetics, metabolism)
• Signal Transduction (drug effects, genetics)
• Treatment Outcome
• Exome Sequencing
• Xenograft Model Antitumor Assays