Identifying clinical development opportunities for antibody drug conjugates (ADCs) in gastrointestinal (GI) cancers through RNA-expression analysis in 637 cell lines

Abstract

Background: Limited public availability of pan-cancer protein expression data hampers the identification of tumors with sufficient target expression for the successful clinical development of ADCs. We used RNA expression data from 637 cancer cell lines (CCLs), encompassing 22 tumor types, to assess which GI cancers expressed ADC targets (ADCt) at higher levels than an index tumor (IT) type where ADC activity against a specific ADCt has been shown. Our CCL based approach is not confounded by tumor content or expression in stroma, helping the rational identification of GI tumors with high potential for ADC activity. Method(s): RNA expression of 12 ADCt was obtained from the Cancer Cell Line Encyclopedia. For each ADCt, the tumor type where a matched ADC showed the highest clinical/pre-clinical activity was selected as the IT. Expression in 6 GI cancers (CRC n=56 cell lines, PDAC n=48, BTC n=11, HCC n=23, gastro-esophageal adenocarcinoma GEA n=40, esophageal squamous cell carcinoma ESCC n=25) was compared to the IT. Result(s): The percentage of CCLs per GI malignancy with an expression >= median in the IT is shown (Table). Novel results include greater MET expression in 83% of PDAC than median in lung adenocarcinoma where MET ADCs are promising, higher TROP2 expression in 72% of BTC than median in triple-negative breast cancer, higher HER3 expression in 88% of CRC than median in lung adenocarcinoma, and similar median EGFR expression in ESSC to head/neck SCC where EGFR ADCs have activity. Detailed analyses and integration with IT response rates will be shown. Formula presented] Conclusion(s): RNA expression surpassed the median in the IT in multiple GI malignancies that have not previously been identified to express high levels of these ADCt. Further investigation by immunostains or in exploratory trials are warranted. Legal entity responsible for the study: The authors. Funding(s): Has not received any funding. Disclosure: J. Freckelton: Financial Interests, Personal, Sponsor/Funding, Merck-AGITG clinical research fellowship: Merck. L. Flanders: Financial Interests, Personal, Invited Speaker: Bristol Myers Squibb, Merck KGA. M. Gerlinger: Financial Interests, Personal, Invited Speaker, Speaker fees for educational events: BMS, Merck KGA, Takeda, Servier; Financial Interests, Personal, Expert Testimony, Expert advisory role: MSD; Financial Interests, Personal, Other, Expert scientific advice: Roche; Financial Interests, Personal, Stocks/Shares: Vertex; Financial Interests, Institutional, Funding: Bristol Myers Squibb; Financial Interests, Institutional, Invited Speaker: Roche, Merck KG; Financial Interests, Institutional, Invited Speaker, CI role remuneration: AstraZeneca; Non-Financial Interests, Institutional, Other, Provision of research reagents: Roche. All other authors have declared no conflicts of interest.Copyright © 2025