# Establishment and characterization of preclinical models of human gynecologic tract carcinosarcomas demonstrates targetable FGFR1 alterations

## TL;DR

Researchers created preclinical models of gynecologic carcinosarcomas and found that FGFR1 alterations can be targeted for treatment.

## Contribution

Establishment of PDX models and a cell line showing FGFR1 as a potential therapeutic target in carcinosarcomas.

## Key findings

- PDX models and a cell line were developed that preserved the tumor characteristics and genetic profiles of the original carcinosarcomas.
- Recurrent FGFR1 amplification and protein over-expression were identified as targetable alterations in these models.
- AZD4547, an FGFR inhibitor, significantly inhibited tumor growth in models with high FGFR1 amplification.

## Abstract

Gynecologic carcinosarcoma is an uncommon but aggressive malignancy that frequently requires systemic therapy but therapeutic options are limited. Development of preclinical models is therefore important for therapeutic advancement.

Carcinosarcoma tumor (6 uterine and 1 tubo-ovarian) from 7 surgical samples were implanted into immunocompromised mice for patient-derived xenograft (PDX) and/or cell line development. The histologic, immunophenotypic and genetic features were characterized. Based on the observed molecular profiles and targetable molecular alterations, in vivo studies were conducted to evaluate the efficacy of targeted therapy on tumor growth.

We established 1 cell line and 6 PDX models which recapitulated the dominant phenotype of the respective parental tumors with preserved mesenchymal differentiation lineage in the sarcomatous component. Genomically, the PDX/cell line models preserved similar complex pattern of copy number alterations and similar mutation landscape when compared to the respective parental tumors. All 7 parental carcinosarcoma tumors and PDX/cell line models harbored pathogenic TP53 mutations. Moreover, we identified recurrent copy number gain/amplification involving several receptor tyrosine kinases (RTK), including amplification and protein over-expression of FGFR1. In vivo drug evaluation using a small molecule inhibitor (AZD4547) of FGFRs showed significant growth inhibition in the carcinosarcoma PDX tumor with the highest FGFR1 amplification and protein expression whereas AZD4547 showed no significant growth effects on carcinosarcoma lacking high level FGFR1 amplification, indicating oncogenic dependency on the amplified RTK pathway.

These findings demonstrate the utility of patient-derived tumor models in the identification and the functional validation of potentially targetable molecular alterations in preclinical setting.