Investigating mechanistic and therapeutic implications of the LZTR1-RIT1 signaling axis in hepatocellular carcinoma

• Applicant: Professor Dr. Darjus-Felix Tschaharganeh
• Subject Area: Pathology
• Term: since 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 495696666

Hepatocellular carcinoma (HCC) - the most common form of liver cancer - is the second most lethal cancer type. Therapeutic treatment is of limited efficacy and patients with advanced HCC are regularly confronted with a devastating prognosis. Owing to the lack of druggable genetic alterations in tumors and high intertumoral heterogeneity precise targeted therapies for HCC are missing. For example, whereas mutations in genes comprising the RAS/MAPK-pathway, e.g. BRAF or KRAS, are common in many other solid tumor types and can be targeted by specific inhibitors for this pathway, they are absent in HCC. Yet, latest large-scale next generation sequencing studies of HCCs have for the first time revealed frequent loss-of-function mutations in LZTR1 (leucine zipper like transcription regulator 1), a gene very recently shown to act as a negative regulator of the RAS/MAPK-pathway presumably via its impact on RIT1 (Ras Like Without CAAX 1) stability. In fact, by mining publicly available genomic datasets, we observed frequent loss-of-function mutations in LZTR1 as well as frequent RIT1 amplifications in HCC. In this project, we will consequently characterize the functional role of LZTR1 and RIT1 in liver cancer and its potential to serve as a biomarker for MAPK inhibitor treatment in HCC. First, we will investigate LZTR1 and RIT1 expression levels along with markers predictive for MAPK activity in a panel of well-characterized human HCC tumor samples. Moreover, we will determine the molecular and biochemical mechanisms of LZTR1 and RIT1 alterations on MAPK signaling using HCC cell line models. We will then investigate the relation between LZTR1 and RIT1 expression and responsiveness towards drugs affecting MAPK signaling (e.g. clinically used MEK inhibitors) in a panel of human and mouse HCC cell lines. Importantly, we will leverage state-of-the art genomic tools to generate defined genotypes associated with LZTR1 loss-of-function and RIT1 overexpression in murine livers to investigate their cancer-driving role in an autochthonous setting. Here, tumor development occurs directly in the animals’ organ, hence better recapitulating tumor growth in the context of a given tumor microenvironment and the whole organism. We will exploit these HCC mouse models to investigate the responsiveness towards drugs affecting MAPK signaling in vivo. Collectively, this project will clarify the cancer-driving role of LZTR1-RIT1 signaling and could help to establish LZTR1 and RIT1 expression as predictive biomarkers for response towards targeted therapies focusing on MAPK signaling in HCC.

• DFG Programme: Research Grants