Dual Targeting Oncoproteins MYC and HIF1α Regresses Tumor Growth of Lung Cancer and Lymphoma

Simple Summary Both MYC and HIF1 alpha are critical transcriptional factors involved in the initiation, transformation, progression and maintenance in a variety of human tumors, but till now no study indicates whether it is possible to simultaneously targeting both MYC and HIF1 alpha for therapeutics. Here we report that echinomycin simultaneously inhibited MYC and HIF1 alpha through proteasomal degradation. Treatment of echinomycin regressed tumor cell growth both in vitro cultured cells and in vivo mouse models of lung cancer and lymphoma. beta-TrCP and VHL are involved in the degradation of MYC and HIF1 alpha induced by echinomycin, respectively. Our data provided a new approach to target these and potentially other oncogenic proteins for cancer therapy. MYC and HIF1 alpha are among the most important oncoproteins whose pharmacologic inhibition has been challenging for the diverse mechanisms driving their abnormal expression and because of the challenge in blocking protein-DNA interactions. Surprisingly, we found that MYC and HIF1 alpha proteins in echinomycin-treated cells were degraded through proteasome dependent pathways, respectively by the beta-TrCP- or VHL-dependent mechanisms. The degradation is induced in a variety of cancer types, including those with mutations in the p53 tumor and LKB tumor suppressors and the KRAS oncogene. Consistent with inhibition of MYC and HIF1 alpha, administration of echinomycin inhibited growth of lung adenocarcinoma xenograft and a syngeneic lymphoma model in mice. Furthermore, echinomycin efficiently induced regression of syngeneic mouse lymphoma driven by MYC over-expression. Our data demonstrated a new mechanism by which echinomycin simultaneously targets MYC and HIF1 alpha for degradation to inhibit growth of lung cancer and lymphoma. Given the broad impact of beta-TrCP or VHL in stability of oncogenic proteins, echinomycin may emerge as a non-PROTAC (proteolysis targeting chimera) degrader of oncogenic proteins.

Automated summary

Echinomycin inhibits MYC and HIF1 alpha through proteasomal degradation, leading to regression of lung cancer and lymphoma growth.