AMBROGIo lab

Understanding kras-driven tumorigenesis

Projects

Cellular homeostasis is controlled by the RAS-MAPK pathway. This pathway is dysregulated in human diseases, especially cancer, in which more than 50% of cases carry aberrations that hyperactivate the RAS-MAPK signaling. In this context, KRAS mutations are the most frequent oncogenic drivers. Therapeutic suppression of pathogenic KRAS-RAF-MAPK signaling to achieve disease control in cancer patients still represents a challenging target.

Dr. Ambrogio made significant contributions to the understanding of KRAS-driven lung tumorigenesis by focusing on the early stages of tumor progression in vivo (Ambrogio et al, Nature Medicine, 2016) and on the characterization of drug resistance mechanisms of KRAS-mutant cancer cells (Ambrogio et al, Cell, 2018).

The research focus of Chiara Ambrogio’s lab is to characterize in vitro and in vivo the “KRAS signalosome”, defined as the functional protein complex engaging KRAS and related effectors, modulators and adaptors at the cell membrane. In terms of translational impact, the understanding of detailed mechanisms regulating the formation of the KRAS signalosome at the membrane is fundamental to discover new therapeutic strategies for KRAS-mutant cancer.

Other on-going projects in the lab deal with epigenetics&tumor initiating cells, in vivo studies to understand the relevance of RAF kinases localization in cancer cells, therapeutic vulnerabilities of specific KRAS isoforms and PROTAC approaches to degrade KRAS.

Looking for the causal relationship between epigenetics and tumor-initiating events

Unraveling how epigenetic contribution dictates the malignant phenotype of advanced KRAS-driven tumors

characterizing in vitro and in vivo the KRAS signalosome

In terms of functional dynamics and related actionable vulnerabilities

Mysore VP *, Zhou Z *, Ambrogio C *, Wang Q, Okoro J, Jänne PA, Westover KD, Shan Y, Shaw DE. Structural model of a Ras-Raf signalosome . *equally contributed. bioRxiv, doi: https://doi.org/10.1101/2020.07.15.165266

ASSESSING THE THERAPEUTIC VALUE OF INHIBITING KRAS CLUSTERIZATION IN VIVO

Generation of a new double-conditional KRAS-driven GEMM to study the role of dimerization in vivo and to inhibit KRAS dimerization as a new therapeutic avenue

Relevance of RAF kinases localization at the membrane as key feature to sustain oncogenic MAPK activity in vivo

Generation of GEMM models where wild-type RAF proteins are replaced by inducible membrane bound isoforms to understand whether any RAF-bound isoform phenocopies mutant KRAS in vivo and/or is responsible for tissue-specific tumorigenic process

study OF biochemical and signaling differences between mutant KRAS isoforms

Deciphering the differences between distinct KRAS activating mutations in terms of downstream signaling and drug sensitivity to contribute to potential patient stratification criteria

on-target and off-target mechanisms of resistance to G12C inhibitors

Defining mechanisms of resistance to G12C inhibitors by combining anti-KRAS PROTAC technology and drug screenings