# Expression of antibody–drug conjugate targets in soft tissue sarcomas

## TL;DR

This study maps ADC target expression in soft tissue sarcomas, revealing opportunities for new therapies based on gene expression patterns.

## Contribution

The largest molecular epidemiology study of ADC target expression in soft tissue sarcomas, identifying new therapeutic opportunities.

## Key findings

- ADC targets are heterogeneously expressed across and within soft tissue sarcoma types.
- PTK7 is overexpressed in 81% of liposarcomas, suggesting a potential new therapeutic target.
- Co-expression of ADC targets with vulnerabilities to immune checkpoint inhibitors and other therapies was observed.

## Abstract

Soft tissue sarcomas (STSs) are aggressive and heterogeneous tumors with few efficient systemic therapies. Antibody–drug conjugates (ADCs) represent an emerging therapeutic option in oncology. Their efficacy is dependent on the expression of the ADC target on tumor cells. Very few data are available on ADC target expression in STSs.

We analyzed the mRNA expression of 62 targets and 60 genes potentially involved in resistance/response to ADC in 1664 clinical primary tumors, including 476 liposarcomas (LPSs) 341 leiomyosarcomas, 330 undifferentiated pleomorphic sarcomas, 286 gastrointestinal stromal tumors, 126 synovial sarcomas, and 105 myxofibrosarcomas. Tumor expression in each type was compared with expression in 7414 normal tissue samples. To confirm the results at the protein level, we applied immunohistochemistry (IHC) to four ADC targets in another series of STS samples.

Expression profiles of ADC targets were heterogeneous across and within all STS types. All types expressed multiple ADC targets. An overexpression rate of at least 25% of samples in at least one type was observed for 41 targets. The high target overexpression rate in some STS types suggested numerous new therapeutic opportunities not currently studied in clinical trials, such as PTK7 overexpressed in 81% of LPSs. In addition, co-expression of ADC-target pairs and of targets with signatures of vulnerability to immune checkpoint inhibitors, poly (ADP-ribose) polymerase (PARP) inhibitors, and cyclin-dependent kinase (CDK)4/6 inhibitors was evidenced in the different pathological types, suggesting opportunities for testing ADC-based combinations. Finally, we showed heterogeneous expression profiles of potential ADC resistance/response genes between and within STS types. IHC confirmed the mRNA results for the four tested targets.

STSs express multiple target genes relevant for ADC treatment and expression varies between and within the pathological types. This comprehensive ADC target landscape, based on the largest molecular epidemiology study in STS, should help clinicians and drug developers for further evaluation of ADCs across STS types.

•Expression of 62 ADC targets and 60 “potential response” genes in 1664 clinical STS and 7414 normal tissue samples.•Heterogeneous expression profiles of ADC targets between and within six major STS types.•High overexpression rate of some ADC targets in some STS types.•Co-expression of ADC-target pairs and of ADC targets with signatures of vulnerability to ICI or targeted therapies.•Heterogeneous expression of potential ADC resistance/sensitivity genes across and within STS types.

Expression of 62 ADC targets and 60 “potential response” genes in 1664 clinical STS and 7414 normal tissue samples.

Heterogeneous expression profiles of ADC targets between and within six major STS types.

High overexpression rate of some ADC targets in some STS types.

Co-expression of ADC-target pairs and of ADC targets with signatures of vulnerability to ICI or targeted therapies.

Heterogeneous expression of potential ADC resistance/sensitivity genes across and within STS types.