Fig. 1

Tretinoin sensitises AB1-HA murine mesothelioma to cyclophosphamide chemotherapy. (A). The generation of the cyclophosphamide (CY) responder signature. Tumors from complete responders and progressors were sequenced and the differentially expressed genes upregulated in complete responders were made into a ‘CY responder gene signature’ (n = 178 genes). (B) Drugs predicted to induce a CY-sensitive tumor microenvironment, as determined by Ingenuity upstream regulatory analysis. (C) Experimental design for tretinoin and CY combination treatment. Mice were inoculated with AB1-HA s.c. and treated with tretinoin i.p. starting 3 days prior to cyclophosphamide and continued for 9 total doses at 10 mg/kg. CY was dosed at 200 mg/kg on day 12. (D) Survival of mice inoculated with AB1-HA and treated with CY, tretinoin or the combination (n = 10) (E) Heatmap of complete responders (CR) and progressors (PR) to CY treatment clustered using a ‘tretinoin induced genes’ set. (F) Gene set enrichment analysis of tretinoin associated gene sets in complete CY responders or progressors. Positive NES indicated a gene set is enriched in complete responders. Significance was determined using the Mantel-Cox log-rank test. *p < 0.05 **p < 0.01