Amplified LZK is a novel therapeutic target in esophageal squamous cell carcinomas with 3q amplicon

Authors

• T Nguyen
• S Park
• A Gandjbakhche

Abstract

Esophageal Squamous cell carcinoma (ESCC) is the dominant histological type (90%) of esophageal cancers worldwide. The estimated global frequency is 512,000 new cases, with a 5-year survival rate of less than 25%, ranking it as one of the deadliest cancers with an urgent need for new therapies. Copy number alterations are frequently observed in ESCCs. Distal amplification of chromosome 3 (3q26-3q29, the 3q amplicon) occurs in 35% of ESCC patients. One of the most frequently amplified genes residing on chromosome 3 is MAP3K13, which encodes the Leucine Zipper-bearing Kinase (LZK). The focus of our research is to examine whether amplified LZK can serve as a therapeutic target in ESCC cells harboring the 3q amplicon. Through dox-inducible shRNA knockdown of LZK, we validated MAP3K13 as a novel oncogenic driver required to maintain the proliferation and cell survival of ESCC cells with 3q amplicon. We then tested pharmacological inhibitors of LZK and established several lead LZK inhibitors that abolish LZK kinase activity and reduce tumorigenic phenotypes of ESCC cell lines harboring amplification compared to control cell lines. Furthermore, these effects were rescued by a drug-resistant mutant form of LZK, confirming the specificity of LZK inhibitors. Importantly, LZK inhibitors suppressed in vivo tumor growth in PDX models with amplified LZK. Finally, we identified LZK as an upstream regulator of the oncogene Akt, where catalytic inhibition of LZK suppresses Akt expression in ESCCs with the 3q amplicon. This research has far-reaching implications as it identifies LZK is a new pharmacological target in ESCCs.

Scientific Focus Area: Cancer Biology

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