Abstract 7266: VGLL4 is the target of the 3p25 homozygous deletion and presents a novel therapeutic vulnerability for TEAD1/4 but not TEAD1 inhibitors
Authors: Muller Florian , Kunnimalaiyaan Selvi , Mangrolia Parth , Olson Jill 
Published: March 2024

Abstract
The Hippo pathway, a critical cell proliferation regulator, remains an underexplored oncogenic pathway in precision oncology. It is executed through YAP1/TAZ co-activators and the TEAD transcription factor family (TEAD1-4), driving expression of tumor-promoting genes. Palmitic acid site TEAD inhibitors have shown strong pre-clinical and clinical activity, but identification of genetic markers of vulnerability and patient selection remain an urgent and open question. Sporos undertook a broad bioinformatic analysis of Hippo pathway components and regulatory genes to identify genetic alterations that drive TEAD activity and potentially act as targetable vulnerabilities. Here, we present a key finding from this investigation. The 3p25 locus undergoes frequent homozygous deletion in solid tumors especially lung squamous cell carcinoma. While VHL was long assumed to be the target tumor suppressor gene of this deletion - we show that VGLL4 is in the only gene in the peak of GISTIC statistically significance in lung squamous cell carcinoma and VGLL4 and ATG7 are both in the peak in Renal Clear Cell Carcinoma (RCC). These data unambiguously establish that VGLL4 deletion is a major oncogenic driver in lung squamous cell carcinoma (SCC) and a contributor in RCC. Because VGLL4 is the major negative relator of the YAP/TEAD transcriptional complex and directly competes with YAP for TEAD binding - we hypothesize that Lung SCC with VGLL4-homozygous deletion would be uniquely dependent on YAP/TEAD activity and show selective sensitivity to TEAD inhibitors. While we were unable to locate a Lung SCC VGLL4-deleted PDX, we identified a VGLL4/ATG7 homozygous deleted RCC PDX, KI2552, in the CrownBio collection. We show that treatment with SPR1, Sporos’s novel TEAD1/4 inhibitor, decreases tumor growth and dramatically extends survival of mice bearing VGLL4/ATG7-deleted KI2552 RCC PDX. On the other hand, VT103, a strong TEAD1 inhibitor which shows comparable pre-clinical activity to SPR1 in the NCI-H226 mesothelioma CDX - did not show any activity in KI2552 PDX. These data emphasize the importance of targeting paralogs besides TEAD1 to broaden anti-neoplastic activity beyond mesothelioma and suggest that VGLL4-homozygous deletion confers TEAD inhibitor sensitivity even in carcinomas where it isn’t the principal driver and portent exceptionally anti-neoplastic activity in neoplasms where it is. Given the wide distribution of the 3p25 homozygous deletion - our findings open a large new potential responder population to TEAD inhibitors and warrant inclusion of VGLL4 in NSG diagnostic sequencing panels.
Citation Format: Florian Muller, Selvi Kunnimalaiyaan, Parth Mangrolia, Jill Olson. VGLL4 is the target of the 3p25 homozygous deletion and presents a novel therapeutic vulnerability for TEAD1/4 but not TEAD1 inhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7266.