Data from SMAD4 Deficiency Promotes Pancreatic Cancer Progression and Confers Susceptibility to TGFβ Inhibition

<div>Abstract<p>The 5-year overall survival rate for pancreatic cancer remains ∼13%, underscoring the urgent need for improved treatment strategies. TGFβ is a promising target due to its significant involvement in the desmoplasia, immune suppression, and chemoresistance characteristics of pancreatic cancer. More than 300 clinical trials targeting TGFβ have been conducted in unselected patient cohorts; however, none of the therapies have gained FDA approval. Nevertheless, TGFβ blockade may hold promise for a subset of cancers with nonfunctional TGFβ signaling. More than 25% of pancreatic cancers carry mutations in <i>SMAD4</i>, a key component of canonical TGFβ signaling. In this study, we investigated the potential for stratifying patients based on <i>SMAD4</i> mutational status to identify tumors susceptible to TGFβ inhibition. Analysis of SMAD4 expression in human pancreatic tumors revealed that SMAD4 mutation or loss is associated with worse disease-free survival. Intriguingly, intratumoral SMAD4 expression displayed heterogeneity among human pancreatic cancer samples. <i>SMAD4</i>-deficient genetically engineered mouse models and orthotopic <i>SMAD4</i> knockout tumor models exhibited reduced survival, increased metastasis, and alterations in the tumor microenvironment compared with <i>SMAD4</i> wild-type controls, consistent with gene and protein expression changes in the absence of functional SMAD4. Importantly, treating mice bearing <i>SMAD4</i>-deficient tumors with a blocking TGFβ antibody reduced tumor weight and improved survival. These findings suggest that genomic stratification by TGFβ axis alterations, such as <i>SMAD4</i> mutations, may be a promising approach to identifying patients likely to benefit from a TGFβ inhibitor.</p>Significance:<p>Targeting TGFβ in pancreatic cancers that are deficient in canonical TGFβ signaling could provide a therapeutic strategy to enhance standard and immune therapy approaches for a substantial population of pancreatic cancer patients.</p></div>