The association between different molecular alterations in Wnt/β-catenin signaling and response to treatment with immune checkpoint inhibitors in solid tumors

Background The wingless/integrated (Wnt)/β-catenin signaling plays an essential function in immune cell modulation and is considered a notable potential mechanism of immune escape and resistance to immune checkpoint inhibitors (ICIs). Here, we explored the association between different molecular alterations in Wnt/β-catenin signaling and the response to treatment with ICIs in solid tumors.Methods The cBioCancer Genomics Portal was used to obtain genomic data. The prevalence of different molecular alterations (SFRP1 SFRP2 SFRP4 SFRP5 SOST TCF7L1 TLE1 TLE2 TLE3 TLE4 WIF1 ZNRF3 CTNNB1 AMER1 APC AXIN1 AXIN2 DKK1 DKK2 DKK3 DKK4 GSK3B RNF43 TCF7 TCF7L2) in Wnt/β-catenin signaling was explored in the Tumor Mutational Burden and ICI cohort comprising a total of 1661patients. This cohort includes patients with cancers of the colon, skin (melanoma), gastroesophageal, lung, unknown primary, bladder, head and neck, breast, brain, and kidney who had received at least one dose of ICIs. For survival analysis, Kaplan-Meier survival curves were generated and compared using log-rank test.Results The prevalence of APC, CTNNB1, RNF43, TCF7L2, AMER1, AXIN1, AXIN2 and GSK3B was 7%, 3%, 2%, 1%, <1%, <1%, <1% and 0% respectively. The rest of the molecular alterations were not profiled. The median overall survival (mOS) in patients with Wnt/β-catenin compared to patients without Wnt/β-catenin alterations was 18 m vs 18 m (P=0.398). Compared to patients without Wnt/β-catenin alterations, the mOS was 17m vs. 18 m (p=0.757) in APC mutations (N=110), 13m vs. 18m (0.660) in CTNNB1 mutations (N=42), NR vs 18 m (P=0.0264) in RNF43 mutations (N=33), 34m vs. 18m (P=0.759) in TCF7L2 mutations (N=19), 34m vs. 18m (P=0.291) in AMER1mutations (N=11), NR vs 18 m (P=0.674) in AXIN1 mutations (N=10) and NR vs 18 m (P=0.170) in AXIN2 mutations (N=12). When cancer types and KRAS mutation status were adjusted for a multivariable Cox regression analysis, RNF43 alterations were an independent predictive biomarker of response to ICIs (P = 0.015; hazard ratio, 2.45; 95% CI, 1.19-5.04).Conclusions In a large cohort of ICI-treated patients, RNF43 mutations were associated with better mOS compared to patients without alterations in Wnt/β-catenin signaling. TCF7L2, AMER1, AXIN1, and AXIN2 mutations were associated with numerically longer mOS but it was not statistically significant. APC and CTNNB1 mutations were associated with numerically worse mOS but it was not statistically significant. If confirmed/validated in larger datasets, the distinction between different molecular alterations in Wnt/β-catenin signaling may help with patients selection for treatment with the combination of ICIs and Wnt/β-catenin targeted therapy.