Comparative assessment of intratumoral sunitinib distribution and therapeutic response in matched primary and metastatic tumor models.

Patients with lung metastases frequently receive anti-angiogenic (AA) therapies based on the histological characteristics of the primary tumor. However, clinical benefit remains limited, suggesting the presence of therapeutic resistance. The contribution of intratumoral drug distribution to this limited therapeutic benefit remains insufficiently understood. We aimed to determine whether differences in therapeutic response are associated with differences in intratumoral drug distribution in matched primary and lung metastasis models of breast and renal cell carcinoma. Matched primary and lung metastasis models were established using 4T1, MDA-MB-231, and RENCA cells. Mice received sunitinib or vehicle, and therapeutic response was evaluated by complementary histopathological analyses of tumor growth, microvessel area (MVA), hypoxia, and necrosis, together with matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI) assessment of intratumoral sunitinib distribution. Sunitinib significantly inhibited tumor growth and reduced MVA in all primary tumor models. In metastasis models, MVA was also significantly reduced, whereas therapeutic response varied between tumor types. MALDI-MSI demonstrated higher normalized intratumoral sunitinib signal in metastases than in corresponding primary tumors, particularly in the breast cancer models. Drug signal also differed between viable, necrotic, and hypoxic tumor regions, demonstrating substantial intratumoral heterogeneity. These findings demonstrate that integrating MALDI-MSI with histopathological analyses enables comparative assessment of intratumoral drug distribution in matched primary and metastatic tumor models. Despite consistent anti-vascular effects and detectable intratumoral drug signal, additional mechanisms beyond inadequate drug delivery are likely to contribute to the limited response observed in breast cancer lung metastases.