Abstract A18: Establishment and characterization of serial patient derived xenograft models representing erlotinib sensitive/resistant non-small cell lung cancer
Authors: Wick Michael J. J. , Helman Elena , Vaught Teresa L. , Farley Monica , Gamez Lizette , Moriarty Alyssa , Ulmer Scott , Tolcher Anthony W. , Rasco Drew W. , Clark Michael , Patnaik Amita , Papadopoulos Kyriakos P. 
Published: May 2016

Background: A subset of non-small cell lung cancer (NSCLC) is driven by mutations or deletions in the epithelial growth factor receptor (EGFR). Several targeted therapies including gefitinib and erlotinib are initially effective towards EGFR-mutant NSCLC; however, resistance to therapy often occurs during the course of treatment. To better understand the mechanisms for resistance to targeted therapies in EGFR-mutant NSCLC we collected tissue from a patient prior to and following response and progression to erlotinib and established xenografts for preclinical drug screening. Clinical and PDX tissue were characterized and compared using DNA and RNA analysis and the models compared in vivo for sensitivity to erlotinib and other therapies.

Methods: The NSCLC adenocarcinoma PDX models were established in CB17 SCID mice using tissue collected from a lung biopsy (ST551) or ascites (ST551C). Clinical tissue, patient blood and the PDX model were subjected to WGS sequencing using an augmented and content-enhanced exome. The augmented exome is optimized to detect major cancer mutations by enhancing coverage over known sequencing gaps and GC-rich regions across &gt;1300 cancer and 200 miRNA genes. We also performed whole-transcriptome sequencing on the PDX model. All data were analyzed using a cancer bioinformatics pipeline optimized for high accuracy detection of small variants and indels, somatic copy-number aberrations, gene expression and fusions. Drug sensitivity studies were performed evaluating sensitivity of the model to patient's current clinical treatment and relevant targeted therapies; study endpoints included tumor volume and time from treatment initiation with tumor growth inhibition, delay and regression reported at study completion. In erlotinib efficacy studies the therapy was administered daily via oral gavage at 35 mg/kg for sixty days.

Results: Genomic analysis identified several variants which were confirmed by transcriptome data including the previously identified EGFR deletion as well as an MGMT deletion. Efficacy studies reported activity of erlotinib towards the ST551 model with a tumor growth inhibition of 112% including tumor regressions during treatment. However erlotinib was found less activity towards the ST551C model with a tumor growth inhibition of 55% and no tumor regressions.

Conclusion: We have established a pair of PDX models from the same patient representing erlotinib sensitive and resistant NSCLC and have characterized the model using comparative genomic analysis and in in vivo efficacy testing. These models can be utilized to better understand mechanisms of resistance to EGFR-targeted therapies and represent unique tools in developing novel therapies to EGFR resistance.

Citation Format: Michael J. J. Wick, Elena Helman, Teresa L. Vaught, Monica Farley, Lizette Gamez, Alyssa Moriarty, Scott Ulmer, Anthony W. Tolcher, Drew W. Rasco, Michael Clark, Amita Patnaik, Kyriakos P. Papadopoulos. Establishment and characterization of serial patient derived xenograft models representing erlotinib sensitive/resistant non-small cell lung cancer. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr A18.