Multiomics characterization of lung metastasis formation and resistance to anti-angiogenesis therapy in renal cell carcinoma

Abstract Purpose Patients with clear cell renal cell carcinoma (ccRCC) often develop lung metastases (LuM) years after curative surgery. The choice of treatment measures and timing for ccRCC-LuM is still controversial. The cause for differential responses of primary ccRCC and LuM to anti-angiogenesis (AA) treatment remains unknown. Methods In a longitudinal cohort study, clinical data of 44 ccRCC-LuM patients (2012–2024) was collected to clarify differential responses of primary ccRCC and LuM to AA treatment. In another profiling cohort, whole-exome and bulk RNA sequencings were performed using primary ccRCC and LuM samples from 8 ccRCC-LuM patients (2013–2020) to unravel potential mechanisms. Results Of 52 participants, 12 (23%) were women and the mean (SD) age was 57.6 (8.7) years. The local disease control rate of LuM lesions was significantly lower than that of primary ccRCC lesions (77% vs. 95%). LuM foci had a poorer local progression-free survival (9[95%CI: 6–12] months vs. 33[95%CI: 17–49] months). Mutation and expression differences between primary ccRCC and LuM for enzymes associated with methylation were striking. The primary ccRCC might be good at performing epithelial-mesenchymal transition while LuM focuses on the secretion of surfactant proteins as a shield from drugs. The molecular spectrum of locally advanced cases showed punctuated evolution, suggesting the possibility of rapid progression. Conclusions We reported the possible mechanisms of ccRCC-LuM formation and resistance to AA therapy, which might result from a series of methylation cascades. Timely surveillance and local treatment are crucial to ccRCC-LuM behaving as solitary or oligo-metastasis.