Advanced Squamous Cell Carcinoma (SCCs) is a common epithelial malignancy. Unfortunately, approximately 1500 Australians die every year as a consequence of drug resistant SCC. Thus, identifying actionable targets that drive drug resistance will lead to improved cure rates in SCC. We previously showed that E2F dysregulation is common in SCC and leads to increases in sphingosine-1-phosphate, Rac1 and AKT which drive anthracycline resistance (1,2). However, the molecular basis for the dysegulation of this axis in SCC remains unclear.
We now show that the expression of Sphk1 in normal keratinocytes is controlled by the ratio of the activating transcription factor, E2F1 and the inhibitory transcription factor, E2F7 (inhibitor). Significantly, we show that in a large fraction of human SCCs and SCC cell lines that E2F7 is selectively exported from the nucleus in a CRM1-dependent manner. Moreover, we show that activation of CRM1 is controlled by the E2F:Sphk1 axis. Thus, we provide the first in vitro and in vivo data showing that dysregulation of the E2F:Sphk1 axis in SCC leads to the selective export of E2F7 from the nucleus and derepression of E2F target genes. In addition, we show that activation of the E2F:Sphk1:CRM1 axis also leads to nuclear export of the anthracycline target, Toposiomerase 2A (Topo2a). Significantly, we show that pharmacological inhibitors of Sphk1 (SK1-I) or CRM1 (selinexor) reinstated nuclear expression of E2F7 and Topo2a and sensitised SCC cells to the cytotoxic action of doxorubicin in vitro and in vivo. Thus, we have identified a novel actionable pathway in human SCCs that drives resistance to anthracyclines. Significantly, we provide proof of concept for a novel drug combination, using clinically available drugs, that could be trialed in SCC patients with curative intent.