Abstract A019: The role of KRAS ubiquitination in lung cancer heterogeneity

Abstract

Abstract Lung cancer is the most frequent cancer with an aggressive clinical course and high mortality rates. About 30% of non-small lung cancer is driven by activating mutations in KRAS (Kirsten rat sarcoma virus). KRAS signaling is tightly controlled through a series of post-transcriptional mechanisms, whereas dysregulation of KRAS activity is translated into heterogeneous clinical behavior. We, and others, have recently implicated leucine zipper-like transcriptional regulator 1 (LZTR1), an adaptor of the CUL3-containing E3 ligase complex, in the control of RAS ubiquitination. Heterozygous loss of LZTR1 is found in one-third of lung adenocarcinomas and co-occurs with oncogenic KRAS mutations, suggesting that LZTR1 loss could contribute to lung cancer by modulating KRAS signaling and affecting the drug response. Both WT and oncogenic KRAS mutant protein levels were modulated by LZTR1 according to a Global protein screen (GPS) scoring regulators of KRAS stability. LZTR1 also directly ubiquitinated mutant KRAS in lung cancer cells. To assess the impact of LZTR1 on KRAS-driven lung cancer, we then used the Kras-G12D mouse model. We found that either homozygous, or heterozygous knockout of Lztr1 cooperates with oncogenic KRAS and promotes tumor initiation and progression at early stages of lung cancer development. The observed phenotype arises from the changes of the immune tumor microenvironment mediated by the differential activation of RAL-B (Ras-related protein Ral-b) signaling in the absence of LZTR1. These results shed a novel light on the crosstalk between dysregulation of KRAS ubiquitination, paracrine communication exerted by the cancer cells through secreted cytokines, and the immune response in lung cancer, which has thwarted the effectiveness of therapy to date. Citation Format: Tonci Ivanisevic. The role of KRAS ubiquitination in lung cancer heterogeneity [abstract]. In: Proceedings of the AACR Special Conference: Targeting RAS; 2023 Mar 5-8; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Res 2023;21(5_Suppl):Abstract nr A019.