Abstract 4927: Translational genomics analyses of cholangiocarcinoma identify patients who may respond to tyrosine kinase inhibitors
Authors: Andersen Jesper Boeje , Gillen Matthew , Conner Elisabeth A. , Factor Valentina M. , Thorgeirsson Snorri S. 
Published: August 2012

Background & Aims: Cholangiocarcinoma (CCA) is a heterogeneous disease with poor outcome that accounts for 5-10% of primary liver cancers. We recently developed a characterization strategy using 104 resected CCAs. Patients were classified into two distinct subclasses, based on overall survival, early recurrence, and KRAS mutations. Class comparison identified 4 survival subgroups (SGI-IV). Significantly, SGIII, the patient group with the worst prognosis, was characterized by genes associated with proteasomal activity and inflammation. Microdissection of tumor compartments and immunostaining showed a prevalent deregulation of HER2, EGFR and MET which suggests that select groups of patients may respond to tyrosine kinase inhibitors (TKIs) in combination with anti-inflammatory drugs. Methods: We applied integrative and translational genomics by combining data from our patient cohort and 7 human CCA cell lines to investigate optimal treatment options for subgroups of CCA. CCA lines were exposed to TKIs, trastuzumab and lapatinib, and the anti-inflammatory drug celecoxib. Targets were validated by transcriptomics, Western and immunostaining. The efficacy of co-administering celecoxib and trastuzumab was examined in vitro and in a model of TKI-resistant xenografts (30mg/kg celecoxib gavage bid, 0.45mg/dose trastuzumab i.p. twice weekly). Results: To assess receptor tyrosine kinases (RTKs) as potential drug-targets against CCA, we first integrated the CCA cell lines with our patient cohort to establish concordance between the cell lines and the tumor subclasses. The cells were then exposed to trastuzumab and lapatinib for 7 days. Lapatinib, a dual inhibitor of EGFR and HER2, was significantly more effective showing 50-80% growth inhibition compared to 15-20% inhibition achieved by trastuzumab. Classification was confirmed by transcriptomics separating the line based on drug response. TKI-resistance was observed in 3/7 lines with 2/3 being positive for mutations in KRAS, supporting a link between resistance to TKI-based therapies and activation of KRAS. A combination of celecoxib and trastuzumab was effective in inhibiting growth of TKI-resistant lines in vitro (P &lt; 0.0001). In the xenograft model of TKI-resistant CCA co-administration of celecoxib and trastuzumab significantly inhibited the tumor growth (P &lt; 0.01, q = 3.7) after 2 weeks compared to control tumors and mono-therapies. Conclusion: Our study has provided new insights into both pathogenesis and optimal treatment options for CCA. We identified a subgroup of patients with poor outcome who may benefit from TKIs. Furthermore, TKI-resistance was effectively treated both in vitro and in vivo by co-administration with celecoxib. Our data demonstrates that targeting AKT downstream of KRAS sensitizes TKI-resistant CCA to TKIs, and provides a new treatment option for this currently treatment-refractory cancer.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4927. doi:1538-7445.AM2012-4927