FANCD2 Is a Potential Therapeutic Target and Biomarker in Alveolar Rhabdomyosarcoma Harboring the PAX3–FOXO1 Fusion Gene

Abstract

Purpose Alveolar rhabdomyosarcoma that harbors the PAX3/FOXO1 fusion gene (t-ARMS) is a common and lethal subtype of this childhood malignancy. Improvement in clinical outcomes in this disease is predicated upon the identification of novel therapeutic targets. Experimental Design Robust mouse models were used for in vivo analysis, and molecular studies were performed on xenografts treated in parallel. Two independent patient sets (n=101 and 124) of clinically-annotated tumor specimens were used for analysis of FANCD2 levels and its association with clinical and molecular characteristics and outcomes. Results Our xenograft studies reveal a selective suppression of FANCD2 by m-TOR kinase inhibition and radiosensitization of the t-ARMS line only. In the initial patient set, we show FANCD2 transcript levels are prognostic in univariate analysis, and are significantly associated with metastatic disease and that the co-presence of the translocation and high expression of FANCD2 is independently prognostic. We also demonstrate a significant and non-random enrichment of mTOR-associated genes that correlate with FANCD2 gene expression within the t-ARMS samples, but not within other cases. In the second patient set, we show that on a protein level, FANCD2 expression correlates with PAX3/FOXO1 fusion gene and is strongly associated with phospho-P70S6K expression in cases with the fusion gene. Conclusions Our data demonstrate that FANCD2 may have a significant role in the radiation resistance and virulence of t-ARMS. Indirectly targeting this DNA repair protein, through mTOR inhibition, may represent a novel and selective treatment strategy.

Inhibition of MEK confers hypersensitivity to X-radiation in the context of BRAF mutation in a model of childhood astrocytoma

“…4D). Using an index of skin toxicity previously reported, [40] there was a slight decrease in the cumulative toxicity in the combination treatment arm of this study compared to 10 Gy XRT alone (Fig. 4E).…”

“…Inhibition of TORC1 has been associated with increased sensitivity to XRT, and it was considered that rapamycin‐induced G1 arrest could contribute to the sensitizing effects. We also showed that AZD8055 could enhance the effect of XRT, and that FANCD2 was regulated downstream of TORC1 in part by S6K1/2 activity . It was therefore of interest to determine whether selumetinib could enhance daily fractionated XRT.…”

“…We also showed that AZD8055 could enhance the effect of XRT, and that FANCD2 was regulated downstream of TORC1 in part by S6K1/2 activity. [27,40] It was therefore of interest to determine whether selumetinib could enhance daily fractionated XRT. In a pilot study to define the radiosensitivity of BT-40 xenografts, tumor-bearing mice were irradiated (2 Gy fractions) daily to a total dose of 10, 20, or 30 Gy, as previously described.…”

Recent advances in understanding and managing rhabdomyosarcoma

“…Recent preclinical data have shown that FANCD2 is a potential therapeutic target in fusion-positive alveolar rhabdomyosarcoma. In mouse models, FANCD2 may have a significant role in the radiation resistance of alveolar rhabdomyosarcoma, and offers a possibility for targeting this DNA repair protein through mTOR inhibition [ 7 ]. Targeting of the fusion protein is an area of active research from multiple directions; Jothi et al .…”

Towards understanding topological features of protein interactome map of muscle cancer

“…For instance, it may happen from lung cancer (3). Many biomarkers are assigned for rhabdomyosarcomas (4,5). The identification of the tumor major proteins can be helpful to better understand the muscle cancer mechanisms.…”