Abstract 1184: Modeling mechanisms of resistance of epidermal growth factor receptor (EGFR) mutations to targeted drugs through patient-derived xenografts (PDX) of non-small cell lung cancer (NSCLC)
Authors: Stewart Erin L. , Mascaux Celine , Shakashita Shingo , Panchal Devang , Wang Dennis , Li Ming , Pham Nhu-An , Leighl Natasha , Liu Geoffrey , Shepherd Frances A. , Tsao Ming-Sound 
Published: May 2015

Background: Resistance to small molecule EGFR tyrosine kinase inhibitors (TKIs) is seen in some NSCLC patients with activating EGFR mutations. We evaluated in vivo PDX models for their utility in studying EGFR-targeted drug resistance mechanisms.

Methods: Surgically resected early stage NSCLC tumors were implanted into non-obese diabetic severe combined immune deficient (NOD-SCID) mice. Tumors were passaged and expanded in new mouse hosts once the humane endpoint of 1.5 cm maximum diameter was reached. EGFR TKI treatment was initiated at an average tumor volume of 150mm3. Treatments included daily oral gavage with first and second generation EGFR TKIs, and with weekly intraperitoneally administered cetuximab.

Results: Of the 55 NSCLC tumors with EGFR activating mutations, only 6 engrafted (11%) and could be propagated beyond the first passage, and 4 have been studied for their responsiveness to EGFR-targeted agents. Model 148, developed from a patient who received pre-operative erlotinib, showed intrinsic pan-resistance to all EGFR-targeted therapies despite having an L858R mutation. The corresponding patient did not respond to erlotinib, relapsed after surgery and did not receive additional TKI therapy. Model 137, with an exon19 E746-A750 deletion, recapitulated the patient's response to gefitinib at relapse; this model was sensitive to first and second generation EGFR TKIs. Model 192 also has the exon19 E746-A750 deletion, however it did not recapitulate the patient's observed sensitivity to erlotinib. Selection for a MET amplified population during engraftment may be the cause for the disparate drug sensitivities. Model 164 has a double exon19 L747-T751 deletion and T790M EGFR mutation. Neither patient nor xenograft responded to erlotinib; the xenograft responded to cetuximab. Resistance developed over time to a second generation EGFR TKI; this resistant phenotype was not stable as each subsequent passage of the ‘resistant’ tumor exhibited the same initial response pattern. Two potential mechanisms for this transient sensitivity are currently being investigated: epigenetic mechanisms and intratumoural mutational heterogeneity.

Conclusions: PDX models may provide important insight into biomarkers and mechanisms of resistance to targeted therapies, and provide a means to test novel treatment strategies to improve future treatment efficacies.

Citation Format: Erin L. Stewart, Celine Mascaux, Shingo Shakashita, Devang Panchal, Dennis Wang, Ming Li, Nhu-An Pham, Natasha Leighl, Geoffrey Liu, Frances A. Shepherd, Ming-Sound Tsao. Modeling mechanisms of resistance of epidermal growth factor receptor (EGFR) mutations to targeted drugs through patient-derived xenografts (PDX) of non-small cell lung cancer (NSCLC). [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1184. doi:10.1158/1538-7445.AM2014-1184