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

Abstract

MYC and HIF1α 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 HIF1α proteins in echinomycin-treated cells were degraded through proteasome dependent pathways, respectively by the β-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 HIF1α, 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 HIF1α for degradation to inhibit growth of lung cancer and lymphoma. Given the broad impact of β-TrCP or VHL in stability of oncogenic proteins, echinomycin may emerge as a non-PROTAC (proteolysis targeting chimera) degrader of oncogenic proteins.

Pharmacological or genetic inhibition of hypoxia signaling attenuates oncogenic RAS-induced cancer phenotypes

“…Furthermore, we showed echinomycin was particularly effective in multiple oncogenic RAS human leukemia lines compared to non-RAS cell lines and demonstrated its effect in a mammalian in vivo model for oncogenic RAS (xenograft mouse model using human THP1 cells with oncogenic NRAS G12D ; Figure 7). In addition, our recent Disease Models & Mechanisms • DMM • Accepted manuscript data showed echinomycin also effectively inhibited HIF1A oncoprotein and regressed lung tumor cell growth; based on multiple RAS cell lines, including NCI-H727 (KRAS G12V ), NCI-H1944 (KRAS G13D ) and Calu-1 (KRAS G12C ) (Huang et al, 2021).…”

Hypoxia in Uterine Fibroids: Role in Pathobiology and Therapeutic Opportunities

“…Their research demonstrated that both inhibitors were effective in the attenuation of growth and induction of apoptosis of fibroids in vitro and decreased fibroid growth when assessed using in vivo mice models [105]. Echinomycin is a small DNA-binding molecule in the quinoxaline antibiotic family and has been shown to specifically inhibit the activity of HIF-1 and lead to proteasomal degradation of HIF1-alpha [106][107][108]. Similarly, PX-478 is an orally active small molecule that has been shown to inhibit the translation of HIF1-alpha in both hypoxic and normoxic conditions [109].…”

Beta-Transducin Repeats-Containing Proteins as an Anticancer Target

“…• inhibits the expression of β-TrCPs, leading to reduced lung adenocarcinoma and lymphoma tumor growth by blocking the expression of the MYC and HIF-1α proteins [231] Erioflorin β-TrCP1…”