Autophagy inhibition overcomes sorafenib resistance in S45F‐mutated desmoid tumors

Abstract

Background Desmoid tumors (DTs) are rare and understudied fibroblastic lesions that are frequently recurrent and locally invasive. DT patients often experience chronic pain, organ dysfunction, decrease in quality of life, and even death. Methods Sorafenib has emerged as a promising therapeutic strategy, which has led to the first randomized phase 3 clinical trial devoted to DTs. Concurrently, we conducted a comprehensive analysis of sorafenib efficacy in a large panel of desmoid cell strains to probe for response mechanism. Results We found distinctive groups of higher‐ and lower‐responder cells. Clustering the lower‐responder group, we observed that CTNNB1 mutation was determinant of outcome. Our results revealed that a lower dose of sorafenib was able to inhibit cell viability, migration, and invasion of wild‐type and T41A‐mutated DTs. Apoptosis induction was observed in those cells after treatment with sorafenib. On the other hand, the lower dose of sorafenib was not able to inhibit cell viability, migration, or invasion or to induce apoptosis in the S45F‐mutated DTs. The investigation of autophagy showed the dependency of S45F‐mutated DTs on this pathway as a part of cell survival mechanism. Significantly, when autophagy was inhibited genetically or pharmacologically in the S45F mutant cell strains, sensitivity to sorafenib was restored. Conclusions Our findings suggest that the response to sorafenib differs when comparing S45F‐mutated DTs and T41A‐mutated or wild‐type DTs. Furthermore, the combination of hydroxychloroquine and sorafenib enhances the antiproliferative and proapoptotic effects in S45F‐mutated DT cells, suggesting that profiling β‐catenin status could guide clinical management of desmoid patients who are considering sorafenib treatment.

β-catenin S45F mutation results in apoptotic resistance

“…In desmoid tumors, the S45F mutant β-catenin has been associated with higher recurrence rates, a poor response to meloxicam and decreased progression arrest after imatinib treatment [ 20 – 23 ]. In addition, our group recently showed that sorafenib-induced cell death in S45F mutated desmoid tumors appears to be associated with altered autophagy signaling pathway, and that these S45F mutants are dependent on autophagy as an antiapoptotic mechanism [ 38 ]. Notably, our results showing that apoptosis-related genes are deregulated in S45F mutant desmoid tumors support the hypothesis that these mutants do not rely on apoptosis as a mechanism of cell death and may explain why the autophagy pathway is applicable in these tumors.…”

“…Annexin V-PI staining (BD Biosciences, San Jose, CA, USA) was used to measure cell cycle progression and apoptosis induction as previously described [ 45 ]. Caspase 3/7 apoptosis activity was measured using Incucyte software (Essen Biosciences, Ann Arbor, MI, USA) as previously described [ 38 ]. Briefly, fluorescence of caspase 3/7 substrate was divided by the total number of cells measured using Vybrant® DyeCycle™ Green stain (Life Technologies, Grand Island, NY, USA) to obtain the apoptotic index.…”

Mitophagy Promotes Sorafenib Resistance Through a Hypoxia-Inducible ATAD3A Dependent Axis

“…It is crucial to understand the precise molecular mechanisms underlying sorafenib resistance in order to identify novel therapeutic targets and improve the clinical outcome of HCC patients. Although, sorafenib-induced autophagy contributes to drug resistance, it is unknown whether hyperactivated mitophagy is also involved in sorafenib resistance in HCC [23][24][25]. Regarding hypoxia is a major stimulus of mitophagy and also an important cause of sorafenib resistance [26][27][28], our objective was to determine the potential relationship between mitophagy and hypoxia-induced sorafenib resistance in HCC.…”

miR‐138 mediates sorafenib‐induced cell survival and is associated with poor prognosis in cholangiocarcinoma cells

“…However, patients at an advanced stage are still faced with high rate of recurrence after surgery . Sorafenib, a multi‐tyrosine kinase inhibitor, is known to suppress tumor growth . In a previous study, sorafenib was found to exert an anticancer effect on cholangiocarcinoma, whereas, the chemoresistance was confirmed to worsen the 5‐year survival rate.…”