Genomic stratification based on SMAD4 in pancreatic cancer reveals biological implications of aberrant TGFβ signaling and susceptibility to TGFβ inhibition

Only 13% of newly diagnosed pancreatic cancer cases are surgically resectable, emphasizing the importance of systemic therapy. Yet, the 5-year overall survival rate for pancreatic cancer remains ~13%, underscoring the urgent need for new treatment strategies. TGFβ is a promising target due to its significant involvement in the desmoplasia, immune suppression, and chemoresistance characteristic of pancreatic cancer. Over 300 clinical trials targeting TGFβ have been conducted in unselected patient cohorts; however, none have gained FDA approval. Nevertheless, TGFβ blockade may hold promise for a subset of cancers with non-functional TGFβ signaling. Greater than 25% of pancreatic cancers carry mutations in SMAD4, a key component of canonical TGFβ signaling. In this study, we investigate the potential for stratifying patients based on SMAD4 mutational status to identify tumors susceptible to TGFβ inhibition. Analysis of SMAD4 expression in human pancreatic tumors reveals that SMAD4 mutation or loss is associated with worse disease-free survival. Intriguingly, we observe heterogeneity in intratumoral SMAD4 expression among human pancreatic cancer samples. To investigate the consequences of SMAD4 mutation, we employed SMAD4-deficient genetically engineered mouse models and orthotopic SMAD4 knockout models, which exhibited reduced survival, increased metastasis, and alterations in the tumor microenvironment compared to SMAD4 wildtype controls, consistent with gene and protein expression changes in the absence of functional SMAD4. Importantly, mice bearing SMAD4-deficient tumors treated with a blocking TGFβ antibody exhibited reduced tumor weight and improved survival. These findings suggest that targeting TGFβ signaling in TGFβ-deficient tumors has potential utility in pancreatic cancer.