From the understanding of KRAS-RAF membrane dynamics to new therapeutic strategies in cancer

KRAS mutations are frequently observed in various types of cancer and play a significant role in driving the development and progression of the disease. Despite ongoing efforts to develop effective treatments by targeting different components of the KRAS pathway, such as receptors (RTKs) and downstream effectors (MEK), along with direct inhibitors of KRAS itself, there remains an unmet need for personalized therapies tailored specifically for patients with KRAS-mutant cancers. There is a pressing need for novel approaches and innovative concepts to uncover unforeseen vulnerabilities in the oncogenic KRAS pathway. The main objective of our KARMA proposal is to comprehensively study the "KRAS signalosome," which refers to a functional protein complex comprising KRAS and its associated effectors, modulators, and adaptors at the cell membrane. Understanding the detailed mechanisms governing the formation and function of the KRAS signalosome at the cell membrane is crucial for identifying new therapeutic strategies for KRAS-mutant cancers. With KARMA we hope to open up entirely new avenues of research in the field of KRAS cancer research by generating groundbreaking insights into new biological functions of KRAS. To achieve these goals, innovative approaches have been employed using both in vitro and in vivo KRAS-specific genetic systems. Additionally, we aim to provide valuable insights into the specific functions of different isoforms of the RAF protein family in cancer. The state-of-the-art experimental tools and techniques implemented in this project will establish a comprehensive framework for spatially resolved analysis, with broad applications across various fields of basic and translational cancer research, which ultimately will benefit cancer patients.

In the context of our KARMA project aimed at identifying in a dynamic fashion the functional impact of the KRAS complex assembly and disassembly at the cell membrane, in the past 30 months we focused our activity on relevant questions on KRAS biology related to new potential therapeutic vulnerabilities. We completed a study on the biological and clinical differences between different mutant KRAS isoforms (Ricciuti B, Son J, …, Ambrogio C. Comparative analysis and isoform-specific therapeutic vulnerabilities of KRAS mutations in non-small cell lung cancer. Clinical Cancer Research, PMID: 35091439). We also contributed to a study aimed at characterizing novel features of KRAS A146T mutant compared to conventional KRAS mutants (Puliga E, De Bellis C, …, Ambrogio C, Corso S, Giordano S. Biological and targeting differences between the rare KRAS A146T and canonical KRAS mutants in gastric cancer models. Gastric Cancer, PMID: 38261067) and to a study characterizing KRAS-MYC interaction depending on specific KRAS mutations and LOH status (Entrialgo-Cadierno R, Cueto-Ureña C, …., Ambrogio C, Lecanda F, Vicent S. The phospholipid transporter PITPNC1 links KRAS to MYC to prevent autophagy in lung and pancreatic cancer. Molecular Cancer, PMID: 37210549). In parallel, we participated in a study aimed at generating novel models to evaluate RAS oligomerization. The manuscript is currently under preparation (Zhou Z, Li X, Berlinska E, Vietti Michelina S, Winslow MM, Ambrogio C, Shan Y, Santamaria D, Westover KD. The experimental variables that determine the outcome of RAS oligomerization, manuscript in preparation).
Our team grew since the beginning of the KARMA project and we are now 15 people, including postdocs, PhD fellows, technicians and students. Moreover, we organized dissemination activities such as conferences and seminars in order to share the results of our research with a broader public of non-expert in the field.

Considering that, since the submission of our KARMA project in 2020, the therapeutic landscape of KRAS-driven tumors has dramatically changed due to the FDA approval of two direct KRAS inhibitors, we had to readjust some of our lines of investigation in order to maintain our competitiveness in the field. We have successfully generated and characterized KRAS-driven models of resistance to direct KRAS inhibitors which are in advanced stages of manuscript preparation and/or publication, both as original articles or review/commentary, as indicated here:
• Holderfield M, Lee BJ, Jiang J, Tomlinson A, Seamon K, Mira A, Patrucco E, …, Ambrogio C, Wang Z, Gill AL, Koltun ES, Smith J, Wildes D, Singh M. Concurrent inhibition of oncogenic and wild-type RAS-GTP for cancer therapy. Nature, in press
• Nokin MJ, Mira A, Patrucco E, Cousin S, Ricciuti B, Soubeyran I, San José S, Peirone S, Caizzi L, Vietti Michelina S, Bourdon A, Wang X, Alvarez-Villanueva D, Martínez-Iniesta M, Vidal A, Rodrigues T, García-Macías C, Awad MM, Nadal E, Villanueva A, Italiano A, Cereda M, Santamaría D, Ambrogio C. Novel RAS(ON) inhibitors overcome clinical resistance to KRAS G12C covalent blockade. Nat Comm, under revision
• Baltanas FC, Kramer-Drauberg M, Garcia-Navas R, Patrucco E, Petrini E, Olarte-San Juan A, Rodríguez-Ramos P, Borrajo J, Calzada N, Castellano E, Mair B, Kostyrko K, Hofmann MH, Ambrogio C*, Santos E*. SOS1 inhibitor BI-3406 demonstrates anti-tumor activity comparable to SOS1 genetic ablation in KRAS mutant tumors. Cell Reports Medicine, under revision
• Chiarle R, Ambrogio C. Exploiting signaling rewiring in cancer cells with co-existing oncogenic drivers, Mol Oncol, PMID: 37872865
• Di Federico A, Ricciotti I, Favorito V, Michelina SV, Scaparone P, Metro G, De Giglio A, Pecci F, Lamberti G, Ambrogio C, Ricciuti B. Resistance to KRAS G12C Inhibition in Non-small Cell Lung Cancer. Curr Oncol Rep 2023, PMID: 37378881
• Mira A, Ambrogio C. YAP and TAZ orchestrate adaptive resistance to KRAS inhibitors. Nature Cancer 2023, PMID: 37369836
• Ricciuti B, Mira A, Andrini E, Scaparone P, Michelina SV, Pecci F, Cantini L, De Giglio A, Lamberti G, Ambrogio C, Metro G. How to manage KRAS G12C-mutated advanced non-small-cell lung cancer. Drugs Context 2022, PMID: 36452878

Periodic Reporting for period 2 - KARMA (From the understanding of KRAS-RAF membrane dynamics to new therapeutic strategies in cancer)

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