Squamous Cell Carcinoma Patient-derived Xenograft Research Articles

Molecular parameters impacting the success rate of a lung cancer PDX model.

e20592 Background: Patient-derived xenograft (PDX) models can provide renewable cancer tissue resources, are being increasingly utilized for the molecular characterizations of cancers and preclinical studies on drug activities, and have the potential to advance biomarker identification. Previous research has demonstrated that PDX tumors preserve the histologic and morphologic characteristics and gene expression and mutation patterns of primary tumors, and correlate to patient survival. Tumor histological subtypes and differentiation grades are known to contribute to the success of PDX intake, but little is known about how molecular features associate with the success of PDX engraftment or whether PDX preserves subclonal architecture of primary tumors. Methods: To fill this void, we analyzed 252 primary tumor samples from the SPORE/ICON project at MD Anderson Cancer Center that were used for generating PDXs and had comprehensive genomic, transcriptomic, and immune profiling data available to evaluate the parameters impacting the intake success of lung cancer PDXs. In order to establish the impact of molecular features on PDX intake success we also assessed the fidelity of PDX in representing the molecular features of this cohort of primary tumors. Results: Only 36% of the primary tumors in this study successfully generated a PDX, with Squamous Cell Carcinoma PDX demonstrating an intake rate of 67% and Adenocarcinoma PDX demonstrating an intake rate of 21%. Genomic architecture derived from whole exome sequencing showed not only 43% (38-48%) of mutations shared, but also similar clonal architecture between primary tumors and PDX. Higher copy number aberration burden, high tumor purity and low immune infiltration in primary tumors were found to be associated with successful intake of PDX. Transcriptomics revealed 6,103 genes differentially expressed between primary tumors with successful PDX intake versus those which were unsuccessful. Pathway analysis of these genes indicated that inhibition of cell proliferation, signaling, and migration as well as DNA replication, recombination and repair were associated with PDX intake failure regardless of histology. Conclusions: These findings indicate that PDX intake success is regulated by molecular features and multiomic evaluation of lung cancer primary tumors can be used as a marker for determining which samples to use for PDX model generation.

Characterization and radiosensitivity of HPV-related oropharyngeal squamous cell carcinoma patient-derived xenografts

Background: Oropharyngeal squamous cell carcinomas (OPSCC) are rising rapidly in incidence due to Human Papillomavirus (HPV) and/or tobacco smoking. Prognosis is better for patients with HPV-positive disease, but may also be influenced by tobacco smoking and other factors. There is a need to individualize treatment to minimize morbidity and improve prognosis. Patient-derived xenografts (PDX) is an emerging pre-clinical research model that may more accurately reflect the human disease, and is an attractive platform to study disease biology and develop treatments and biomarkers. In this study we describe the establishment of PDX models, compare PDX tumors to the human original, and assess the suitability of this model for radiotherapy research and biomarker development.Material and methods: Tumor biopsies from 34 patients with previously untreated OPSCC were implanted in immunodeficient mice, giving rise to 12 squamous cell carcinoma PDX models (7 HPV+, 5 HPV-). Primary and PDX tumors were characterized extensively, examining histology, immunohistochemistry, cancer gene sequencing and gene expression analysis. Radiosensitivity was assessed in vivo in a growth delay assay.Results: Established PDX models maintained histological and immunohistochemical characteristics as well as HPV-status of the primary tumor. Important cancer driver gene mutations, e.g., in TP53, PIK3CA and others, were preserved. Gene expression related to cancer stem cell markers and gene expression subtype were preserved, while gene expression related to hypoxia and immune response differed. Radiosensitivity studies showed high concordance with clinical observations.Conclusion: PDX from OPSCC preserves important molecular characteristics of the human primary tumor. Radiosensitivity were in accordance with clinically observed treatment response. The PDX model is a clinically relevant surrogate model of head and neck cancer. Perspectives include increased understanding of disease biology, which could lead to development of novel treatments and biomarkers.

Impact of Tumour Hypoxia on Evofosfamide Sensitivity in Head and Neck Squamous Cell Carcinoma Patient-Derived Xenograft Models.

Tumour hypoxia is a marker of poor prognosis and failure of chemoradiotherapy in head and neck squamous cell carcinoma (HNSCC), providing a strategy for therapeutic intervention in this setting. To evaluate the utility of the hypoxia-activated prodrug evofosfamide (TH-302) in HNSCC, we established ten early passage patient-derived xenograft (PDX) models of HNSCC that were characterised by their histopathology, hypoxia status, gene expression, and sensitivity to evofosfamide. All PDX models closely resembled the histology of the patient tumours they were derived from. Pimonidazole-positive tumour hypoxic fractions ranged from 1.7–7.9% in line with reported HNSCC clinical values, while mRNA expression of the Toustrup hypoxia gene signature showed close correlations between PDX and matched patient tumours, together suggesting the PDX models may accurately model clinical tumour hypoxia. Evofosfamide as a single agent (50 mg/kg IP, qd × 5 for three weeks) demonstrated antitumour efficacy that was variable across the PDX models, ranging from complete regressions in one p16-positive PDX model to lack of significant activity in the three most resistant models. Despite all PDX models showing evidence of tumour hypoxia, and hypoxia being essential for activation of evofosfamide, the antitumour activity of evofosfamide only weakly correlated with tumour hypoxia status determined by pimonidazole immunohistochemistry. Other candidate evofosfamide sensitivity genes—MKI67, POR, and SLFN11—did not strongly influence evofosfamide sensitivity in univariate analyses, although a weak significant relationship with MKI67 was observed, while SLFN11 expression was lost in PDX tumours. Overall, these data confirm that evofosfamide has antitumour activity in clinically-relevant PDX tumour models of HNSCC and support further clinical evaluation of this drug in HNSCC patients. Further research is required to identify those factors that, alongside hypoxia, can influence sensitivity to evofosfamide and could act as predictive biomarkers to support its use in precision medicine therapy of HNSCC.

A subset of esophageal squamous cell carcinoma patient-derived xenografts respond to cetuximab, which is predicted by high EGFR expression and amplification.

Epidermal growth factor receptor (EGFR) is reportedly overexpressed in most esophageal tumors, but most targeted therapies showed no efficacy in non-selected patients. This study aims at investigating the adaptive cetuximab subset in a cohort of esophageal squamous cell carcinoma (ESCC) patient-derived xenografts (PDXs). A large panel of ESCC PDXs has been established. The copy number, mRNA expression and immunohistochemistry (IHC) of key EGFR pathways have been examined along with cetuximab response. A preclinical trial on a randomly selected cohort of 16 ESCC PDXs was conducted, and the genomic annotations of these models were compared against the efficacy readout of the mouse trial. The trial identified that 7 of 16 (43.8%) responded to cetuximab (ΔT/ΔC <0 as responders). The gene amplification and expression analysis indicated that EGFR copy number ≥5 (P=0.035), high EGFR mRNA expression (P=0.001) and IHC score of 2-3 (P=0.034) are associated with tumor growth inhibition by cetuximab, suggesting EGFR may function as a single predictive biomarker for cetuximab response in ESCC. Overall, our results suggest that an ESCC subtype with EGFR amplification and overexpression benefits from cetuximab treatment, which warrants further clinical confirmation.

IL-6 Mediates Cross-Talk between Tumor Cells and Activated Fibroblasts in the Tumor Microenvironment.

The tumor microenvironment (TME) plays a major role in the pathogenesis of multiple cancer types, including upper-gastrointestinal (GI) cancers that currently lack effective therapeutic options. Cancer-associated fibroblasts (CAF) are an essential component of the TME, contributing to tumorigenesis by secreting growth factors, modifying the extracellular matrix, supporting angiogenesis, and suppressing antitumor immune responses. Through an unbiased approach, we have established that IL-6 mediates cross-talk between tumor cells and CAF not only by supporting tumor cell growth, but also by promoting fibroblast activation. As a result, IL-6 receptor (IL6Rα) and downstream effectors offer opportunities for targeted therapy in upper-GI cancers. IL-6 loss suppressed tumorigenesis in physiologically relevant three-dimensional (3D) organotypic and 3D tumoroid models and murine models of esophageal cancer. Tocilizumab, an anti-IL6Rα antibody, suppressed tumor growth in vivo in part via inhibition of STAT3 and MEK/ERK signaling. Analysis of a pan-cancer TCGA dataset revealed an inverse correlation between IL-6 and IL6Rα overexpression and patient survival. Therefore, we expanded evaluation of tocilizumab to head and neck squamous cell carcinoma patient-derived xenografts and gastric adenocarcinoma xenografts, demonstrating suppression of tumor growth and altered STAT3 and ERK1/2 gene signatures. We used small-molecule inhibitors of STAT3 and MEK1/2 signaling to suppress tumorigenesis in the 3D organotypic model of esophageal cancer. We demonstrate that IL6 is a major contributor to the dynamic cross-talk between tumor cells and CAF in the TME. Our findings provide a translational rationale for inhibition of IL6Rα and downstream signaling pathways as a novel targeted therapy in oral-upper-GI cancers.Significance: These findings demonstrate the interaction of esophageal cancer and cancer-associated fibroblasts through IL-6 signaling, providing rationale for a novel therapeutic approach to target these cancers. Cancer Res; 78(17); 4957-70. ©2018 AACR.

Characterization and Radiosensitivity of HPV-Related Oropharyngeal Squamous Cell Carcinoma Patient-Derived Xenografts

The purpose of this study was to create a number of patient-derived xenografts (PDXs) reflecting the heterogeneity of oropharyngeal squamous cell carcinoma (OPSCC) and compare the models with the corresponding human original tumors. Also, we aimed to determine if the PDX model is suitable for radiation therapy research. Fresh tumor biopsies from patients with primary, untreated OPSCC were implanted subcutaneously in immunodeficient mice. PDX tumors were serially transplanted and expanded, producing generations of PDX tumors with identical origin. PDX tumors and their corresponding human original were compared using histology, immunohistochemistry, gene expression profiling and next-generation sequencing (NGS). Radiosensitivity was assayed by subjecting PDX tumors to low-dose irradiation in a growth delay assay (4-8 Gy, single fraction). Tumor specimens from 34 OPSCC patients were xenografted, resulting in tumor growth in 20 cases (59%). However, 8 PDX models had a lymphoma-like histologic and immunohistochemical appearance and were disregarded. Further studies were conducted on 12 valid PDX models that retained histological and immunohistochemical features, yielding a final take-rate of 35%. No differences were noted between the full patient cohort and patients giving rise to valid PDXs with regard to HPV status, smoking or tumor characteristics. Although NGS revealed that valid PDX tumors had a mean of 22 genetic variants more than the original tumor (P<.02), there was a high concordance between PDXs and original tumors, with more than half of genetic variants retained in the PDX, including important driver mutations in TP53, PIK3CA, KMT2D, KMT2C and NOTCH1. Gene expression analysis revealed high concordance between PDX and original tumors with regard to expression of HPV oncogenes E6 and E7. However, there were notable differences in tumor microenvironment parameters with PDX tumors showing higher expression of hypoxia-related genes and lower expression of genes related to inflammation and low-dose irradiation of PDX tumors resulted in a reproducible growth delay. Radiosensitivity studies revealed that the most radiosensitive PDX models were HPV-positive, although one HPV-positive PDX model was relatively radioresistant. It is possible to generate PDX models from OPSCC patients that reflect differences in etiology with regard to HPV and smoking. Most PDX models retain histological and immunohistochemical features as well as important driver gene alterations. There are some differences related to tumor microenvironment and immune response. Overall, the PDX model is a promising high-fidelity research tool that may aid in development of personalized medicine. Perspectives include biomarker development, testing of targeted therapies, and improvement of radiation therapy.

Targeting ornithine decarboxylase (ODC) inhibits esophageal squamous cell carcinoma progression

To explore the function of ornithine decarboxylase in esophageal squamous cell carcinoma progression and test the effectiveness of anti-ornithine decarboxylase therapy for esophageal squamous cell carcinoma. In this study, we examined the expression pattern of ornithine decarboxylase in esophageal squamous cell carcinoma cell lines and tissues using immunohistochemistry and Western blot analysis. Then we investigated the function of ornithine decarboxylase in ESCC cells by using shRNA and an irreversible inhibitor of ornithine decarboxylase, difluoromethylornithine. To gather more supporting pre-clinical data, a human esophageal squamous cell carcinoma patient-derived xenograft mouse model (C.B-17 severe combined immunodeficient mice) was used to determine the antitumor effects of difluoromethylornithine in vivo. Our data showed that the expression of the ornithine decarboxylase protein is increased in esophageal squamous cell carcinoma tissues compared with esophagitis or normal adjacent tissues. Polyamine depletion by ODC shRNA not only arrests esophageal squamous cell carcinoma cells in the G2/M phase, but also induces apoptosis, which further suppresses esophageal squamous cell carcinoma cell tumorigenesis. Difluoromethylornithine treatment decreases proliferation and also induces apoptosis of esophageal squamous cell carcinoma cells and implanted tumors, resulting in significant reduction in the size and weight of tumors. The results of this study indicate that ornithine decarboxylase is a promising target for esophageal squamous cell carcinoma therapy and difluoromethylornithine warrants further study in clinical trials to test its effectiveness against esophageal squamous cell carcinoma.

Abstract 769: In vivo response and molecular characterization of a Caucasian NSCLC squamous cell carcinoma PDX sensitive to FGFR inhibitors

Abstract BACKGROUND: The fibroblast growth factor receptor (FGFR) family are reported to be involved in key cellular processes such as proliferation, differentiation, migration &amp; survival with the deregulation of signalling through genetic modification or amplification being observed in cancer. FGFR1 has been reported to be amplified in squamous cell non-small cell lung cancer (NSCLC) as well as other indications (e.g. breast) and there are several FGFR inhibitors currently in clinical trial. It is therefore essential to develop relevant in vivo models for the development and characterisation of new FGFR agents and/or combination strategies which may prolong benefit and delay the emergence of resistance. METHODS: Patient derived xenograft (PDX) models were maintained subcutaneously in vivo in serial passage and their growth monitored by calliper measurements three times weekly; mice were recruited to treatment groups when the mean tumour volume was approximately 200mm3. Response to treatment was evaluated by tumour growth inhibition in response to FGFR inhibitors such as AZD4547 and chemotherapy. Resistance to both chemotherapy (Paclitaxel/Carboplatin) and AZD4547 in the squamous cell carcinoma (SCC) PDX model, LU6429, was generated in vivo through repeated dosing and the resulting models characterised for their treatment response. Molecular characterisation was carried out by RNA sequencing. RESULTS: A number of novel PDX models have been developed which harbour FGFR amplification and mutations including LU6429, a Caucasian NSCLC SCC PDX model which has modest FGFR1 and FGFR2 amplification and responds to FGFR inhibitors. LU6429 PDX tumours (SCC confirmed by IHC) exhibited reproducible sensitivity to AZD4547 (p&amp;lt;0.001) which was maintained in continuous serial passage and following cryogenic storage. FGFR expression and mutational analysis was assessed in naïve tumours, tumours following continuous AZD4547 treatment and in the acquired chemo-resistance setting. Other models show differential response to FGFR inhibitors. CONCLUSIONS: Pre-clinical models such as LU6429, a novel patient-derived NSCLC SCC xenograft model with moderate FGFR amplification which showed significant sensitivity to the FGFR inhibitor AZD4547, are invaluable in assessing novel agents targeting the FGFR pathway and in the development of new combination strategies which may prevent or overcome resistance. Citation Format: Andrew McKenzie, Nektaria Papadopoulou, Yinfei Yin, Simon Jiang, Jane Wrigley, Jie Cai, Martin Page, Henry Li, Rajendra Kumari. In vivo response and molecular characterization of a Caucasian NSCLC squamous cell carcinoma PDX sensitive to FGFR inhibitors. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 769. doi:10.1158/1538-7445.AM2015-769

Establishment and characterization of esophageal squamous cell carcinoma patient-derived xenograft mouse models for preclinical drug discovery

The purpose of this study was to establish and characterize patient-derived esophageal squamous cell carcinoma xenograft (PDECX) mice for utilization in antitumor drug discovery. A total of 96 esophageal squamous cell carcinoma (ESCC) tissues from Chinese patients were transplanted subcutaneously into immunodeficient mice. Histology, EGFR, K-ras, B-raf, and PIK3CA mutations, and HER2 gene amplifications were analyzed in both patient tumors and mouse xenograft tissues using immunohistochemistry, mutant-enriched liquid chip sequencing and fluorescence in situ hybridization assays, respectively. Furthermore, in vivo efficacy studies using five PDECX mice harboring a variety of genetic aberrations were performed using the chemotherapy agents 5-fluorouracil (5-FU) and cisplatin. Thirty-seven PDECX mouse models were successfully established in immunodeficient mice. Pathological analysis revealed similar histological architecture and degrees of differentiation between patient ESCC and xenografted tumors. No mutations were identified in EGFR, K-ras, and B-raf genes in either xenograft models or patient ESCC tissues. In contrast, PIK3CA gene mutations were detected in 12.5% (12/96) ESCC patients and 18.9% (7/37) PDECX models. Interestingly, patient ESCC tissues exhibiting HER2 overexpression or gene amplification were unable to survive in immunodeficient mice. Further analysis showed that PDECX models carrying HER2 2+ expression had no response to 5-FU/cisplatin, compared with HER2-negative models. In conclusion, a panel of PDECX mouse models, which include PIK3CA mutant and HER2-positive models, was established and characterized thus mimicking the current clinical genetic setting of esophageal carcinoma. The sensitivity of HER2-negative ESCC models to chemotherapy supports stratification approaches in the treatment of esophageal carcinoma patients and warrants further investigation of the impact of PI3KCA on treatment response.

Abstract A142: In vivo response and molecular characterization of a Caucasian NSCLC squamous cell carcinoma PDX sensitive to FGFR inhibitor.

Abstract Introduction: Non-small cell lung cancer (NSCLC) accounts for 85% of lung cancer cases, carries a poor prognosis and remains an area of high unmet need. Despite recent advances in treating defined subsets of NSCLC adenocarcinomas with targeted agents such as erlotinib and crizotinib few advances have been made in the treatment of squamous cell carcinoma (SCC), which accounts for 25% of all NSCLC. Although the incidence of fibroblast growth factor receptor (FGFR) mutations in SCC is modest, amplification of FGFR is well documented and there are several first generation FGFR tyrosine kinase inhibitors (TKI) currently in clinical trials. It is therefore essential to develop relevant in vivo patient-derived xenograft (PDX) models for the development and characterisation of new FGFR agents and/or combination strategies which may prolong benefit and delay the emergence of resistance. Methods: LU6429 is a novel Caucasian NSCLC SCC PDX model which is maintained subcutaneously in vivo admixed with a human stromal cell component. Cohorts of mice were dosed with AZD4547, which is an FGFR TKI undergoing evaluation in the clinic, alone or in combination with chemotherapy (CTx; parallel or serial dosing regimens). The extent of inhibition was measured over several in vivo passages and following cryopreservation/resuscitation. CTx and FGFR TKI resistant models of LU6429 were generated in vivo through repeated dosing and the resulting models characterized for their treatment response. Tumor material was characterized for 50 key oncogenes and mutations by Ion Torrent sequencing, for FGFR1-3 expression and genomic amplification by quantitative PCR and FGFR1-2 by FISH analysis. Immunohistochemistry (IHC) was used to confirm NSCLC subtype and EMT status. Results: LU6429 PDX tumours (SCC confirmed by IHC) exhibited reproducible sensitivity to AZD4547 alone (P&amp;lt;0.001) which was maintained both in continuous serial passage and following cryopreservation (at -196°C). FGFR expression, amplification and mutational analysis were assessed in naïve tumour material, following 10 weeks of continuous dosing and following outgrowth from CTx treatment and correlated with treatment response. Conclusions: LU6429 is a novel patient-derived NSCLC SCC xenograft model with reproducible FGFR TKI sensitivity, which is directly relevant to the clinical setting. This model could be invaluable in assessing novel agents targeting the FGFR pathway and in the development of new combination strategies which may prevent or overcome resistance. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A142. Citation Format: Andrew J. McKenzie, Aaron N. Cranston, Nektaria Papadopoulou, Simon Jiang, Jane Wrigley, Yinfei Yin, Henry Li, Martin Page, Rajendra Kumari. In vivo response and molecular characterization of a Caucasian NSCLC squamous cell carcinoma PDX sensitive to FGFR inhibitor. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr A142.

Abstract 342: In vivo response and molecular characterisation of a NSCLC squamous cell carcinoma PDX model exhibiting reproducible sensitivity to FGFR inhibitors.

Abstract BACKGROUND: Non-small cell lung cancer (NSCLC) accounts for 85% of lung cancer cases, carries a poor prognosis and remains an area of high unmet need. Despite recent advances in treating NSCLC adenocarcinomas with targeted agents such as Erlotinib (Tarceva©) and Crizotinib (Xalkori©) few advances have been made in the treatment of squamous cell carcinoma (SCC), which accounts for 25% of all NSCLC. Although the incidence of fibroblast growth factor receptor (FGFR) mutations in SCC is modest, amplification of FGFR is well documented and there are several first generation FGFR inhibitors currently in clinical trial. It is therefore essential to develop relevant in vivo patient-derived xenograft (PDX) models for the development and characterisation of new FGFR agents and/or combination strategies which may prolong benefit and delay the emergence of resistance. METHODS: LION137 is a novel NSCLC SCC patient-derived xenograft (PDX) model which is maintained subcutaneously in vivo admixed with a human stromal cell component. Cohorts of mice were dosed with AZD4547 alone or in combination with chemotherapy (CTx; parallel or serial dosing regimens). The extent of inhibition was measured over several in vivo passages and following cryopreservation/resuscitation. Response to treatment was evaluated by tumour growth inhibition and waterfall plots. Tumour material was characterised for 50 key oncogenes and mutations by Ion Torrent sequencing and FGFR1-4 expression and genomic amplification by quantitative PCR. Immunohistochemistry (IHC) was used to confirm SCC subtype, EMT status and FGFR expression. RESULTS: LION137 PDX tumours (SCC confirmed by IHC) exhibited reproducible sensitivity to AZD4547 alone (P&amp;lt;0.001) which was maintained both in continuous serial passage and following cryopreservation (at -196°C). FGFR expression and amplification and mutational analysis were assessed in naïve tumour material, following 10 weeks of continuous dosing and following outgrowth from CTX treatment and correlated with treatment response. CONCLUSIONS: LION137 is a novel patient-derived NSCLC SCC xenograft model with reproducible FGFRi-sensitivity which is directly relevant to the clinical setting. This model could be invaluable in assessing novel agents targeting the FGFR pathway and in the development of new combination strategies which may prevent or overcome resistance. Citation Format: Andrew Mckenzie, Aaron Cranston, Phil Mallinder, Nektaria Papadopoulou, Simon Jiang, Kerry Moakes, Yinfei Yin, David Onion, Anna Grabowska, Martin Page, Rajendra Kumari. In vivo response and molecular characterisation of a NSCLC squamous cell carcinoma PDX model exhibiting reproducible sensitivity to FGFR inhibitors. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 342. doi:10.1158/1538-7445.AM2013-342

Abstract 2796: Patient-derived xenograft models reveal a subset of clinically relevant squamous non-small cell lung cancers that respond to targeted EGFR inhibition.

Abstract BACKGROUND: Non-small cell lung cancer (NSCLC) accounts for 85% of lung cancer cases, carries a poor prognosis and remains an area of high unmet need. Despite recent advances in treating NSCLC adenocarcinomas with targeted epidermal growth factor receptor (EGFR) kinase inhibitors, few advances have been made in the treatment of squamous cell carcinoma (SCC), which accounts for 25% of NSCLC. Although the incidence of EGFR mutations in SCC is low, a retrospective clinical study of erlotinib in SCC suggested that a proportion of SCC patients would benefit from treatment with an EGFR inhibitor (Tseng et al., 2012). METHODS: NSCLC samples obtained from untreated patients undergoing surgery were collected with ethical consent, disaggregated and implanted subcutaneously in MF-1 nude mice (Harlan UK) admixed with a human stromal cell component to generate patient-derived xenograft (PDX) models (LION PDX models). Tumour material was diagnosed on the basis of operative histology and immunohistochemistry (IHC) used to confirm histological subtype. IHC was also used to evaluate EGFR expression and tumours characterised for mutations in p53, LKB1, EGFR and K-RAS by direct DNA sequencing. Patient-derived xenografts were maintained in vivo and study cohorts of mice dosed when tumours reached 100-200mm3 with either erlotinib or gefitinib or vehicle placebo. Response to treatment was evaluated by tumour growth inhibition and waterfall plots. RESULTS: We have identified a subset of tumours with squamous histology in our LION panel of patient-derived NSCLC xenografts that respond to treatment with a targeted EGFR inhibitor. Four out of 11 SCC models tested (36%) responded to treatment with either erlotinib or gefitinib with greater than 50% growth inhibition and two SCC models responded with ∼30% growth inhibition. Responses correlated well with EGFR expression. Work to characterise a further 8 LION SCC PDX models is also underway. CONCLUSIONS: These data support the proposition that a significant subset of NSCLC patients with squamous histology may benefit from treatment with targeted EGFR inhibitors. Our LION SCC models could be valuable for biomarker studies to identify the basis of the EGFR inhibitor responder subset and for evaluating new agents in a more clinically relevant setting. Citation Format: Aaron Cranston, Andrew Mckenzie, Phil Mallinder, Simon Jiang, Kerry Moakes, Yinfei Yin, Alex Reece-Smith, Anna Grabowska, Martin Page, Rajendra Kumari. Patient-derived xenograft models reveal a subset of clinically relevant squamous non-small cell lung cancers that respond to targeted EGFR inhibition. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2796. doi:10.1158/1538-7445.AM2013-2796