Molecular oncology

Prof.ssa Chiara Ambrogio PI

She has worked extensively in the area of tumor initiation processes, translational cancer research and pre-clinical evaluation of novel drugs for the treatment of lung cancer.

Main group members

Chiara Ambrogio PI
Enrico Patrucco Lab Director
Alessia Mira Postdoc
Maximilian Kramer-Drauberg Postdoc
Cristina Caffarra Malvezzi Postdoc
Rossella Scardaci Postdoc
Ewa Berlinska Phd Student
Sandra Vietti Michelina Phd Student
Pietro Scaparone Phd Student
Ilenia Savinelli Research Technician
Haiyun Wang Visiting Professor
Ettore Petrini Undergraduate Student
Riccardo Gribaudo Undergraduate Student
Mirco Ricciato Undergraduate Student
Emilia Berardelli Undergraduate Student
Roberto Mignacco Undergraduate Student

Research Activity

The RAS oncogene family consists of four 21-kDa GTPases isoforms (KRAS4A, KRAS4B, HRAS, and NRAS) that are among the most frequently mutated genes in human cancer. Very recently, two direct KRAS inhibitors targeting the G12C mutations have been approved for clinical treatment with modest results due to rapid development of resistance; moreover, there are no effective therapies to specifically treat cancers expressing KRAS mutations other than G12C (Figure 1). As a consequence, an urgent need remains for innovative therapies to improve outcomes for KRAS mutant cancer patients.

One intriguing and still largely unexplored aspect of KRAS biology is the relevance of membrane dynamics for downstream signaling and drug sensitivity. KRAS clustering at the membrane dictates the activation of KRAS signaling. We recently described that KRAS dimerization is essential both for the oncogenic activity of the mutant allele and for the tumor suppressive function of the wildtype allele, but the detailed mechanistic understanding and potential therapeutic value of these findings are still uncovered. Our laboratory is devoted to the in vitro and in vivo characterization of the “KRAS signalosome”, defined as the functional protein complex engaging KRAS and related factors, modulators and adaptors at the cell membrane (Figure 2).

FUTURE RESEARCH PLANS

In parallel to the projects focused on the characterization of the KRAS signalosome and the role of wild-type KRAS as tumor suppressor, we are actively working on other lines of investigation dealing with understanding of the relevance of RAF kinases localization in cancer cells in vivo, the discovery of therapeutic vulnerabilities of specific KRAS isoforms and the characterization of on-target and of-target mechanisms of resistance to KRAS-G12C inhibitors using PROTAC approaches to degrade KRAS.

FUNDING ID (PAST 5 YEARS)

2023-2028: MIUR FARE (Italian Ministry of University and Research)
2023-2024: SRA (Scientific Research Agreement) Roche 2022-2023: Kaerton Foundation-Cancer INNOVA program
2022-2027: AIRC (Italian Association for Cancer Research)
2021-2022: SRA (Scientific Research Agreement) Verastem
2021-2026: ERC Consolidator Grant → 2021-2023: SRA (Scientific Research Agreement) Revolution Medicines
2020-2023: Harvard-Armenise Career Development Grant

SELECTED PUBLICATIONS

Ambrogio C*, Gómez-López G, Falcone M, Villanueva A, Crosetto N, Blasco R, Sánchez-Céspedes M, Ren X, Wang Z, Ding K, Serrano M, Hidalgo M, Santamaría D*, Barbacid M*. Combined inhibition of Ddr1 and Notch signaling as an effective therapeutic strategy for K-Ras-driven/p53-null lung adenocarcinomas. Nat Med. 2016 Feb 8. *Co-corresponding author.

Ambrogio C*, Barbacid M, Santamaría D*. In vivo oncogenic conflict triggered by co-existing KRAS and EGFR activating mutations in lung adenocarcinoma. Oncogene. 2016 Oct 24. *Co-corresponding author.

Nieto P, Ambrogio C, de Esteban L, Gómez-López G, Blasco MT, Yao Z, Marais R, Rosen N, Chiarle R, Pisano DG, Barbacid M, Santamaría D. A B-Raf kinase inactive mutant induces lung adenocarcinoma. Nature. 2017 Aug 2.

Ambrogio C*, Köhler J, Zhou ZW, Wang H, Paranal R, Li J, Capelletti M, Cafarra C, Li S, Lv Q, Gondi S, Hunter JC, Lu J, Chiarle R, Santamaría D, Westover KD, Jänne PA*. KRAS dimerization impacts MEK inhibitor sensitivity and oncogenic activity of mutant KRAS. Cell. 2018 Jan 4. *Co-corresponding author.

Wang H, Lv Q, Xu Y, Cai Z, Zheng J, Chen X, Dai Y, Jänne PA, Ambrogio C* and Köhler J*. An integrative pharmacogenomics analysis identifies CK2 alpha as a promising therapeutic target in KRAS(G12C) mutant lung cancer. EBioMedicine. 2019 Nov;49:106-117. doi: 10.1016/j.ebiom.2019.10.012. Epub 2019 Oct 23. *Colast author.

Zhou Z*, Ambrogio C*, Bera AK, Li Q, Li X, Li L, Son J, Gondi S, Li J, Campbell E, Jin H, Okoro JJ, Xu C, Jänne PA, Westover KD. KRASQ61H signals through MAPK in a RAF dimer-dependent manner in non-small cell lung cancer. Cancer Res. 2020 Jun 30. *equally contributed.

Nokin MJ, Darbo E, Travert C, Drogat B, Lacouture A, San José S, Cabrera N, Turcq B, Prouzet-Mauleon V, Falcone M, Villanueva A, Wang H, Herfs M, Mosteiro M, Jänne PA, Pujol JL, Maraver A, Barbacid M, Nadal E, Santamaría D and Ambrogio C. Inhibition of DDR1 enhances in vivo chemosensitivity in KRAS-mutant long adenocarcinoma. JCI Insight. 2020 Aug 6.

Kramer-Drauberg M and Ambrogio C. Discoveries in the redox regulation of KRAS. The International Journal of Biochemistry & Cell Biology, 2020 Dec 10.

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. Nat Struct Mol Biol. 2021 Oct;28(10):847-857. doi: 10.1038/s41594-021- 00667-6. Epub 2021 Oct 8. *equally contributed.

Ricciuti B, Son J, Okoro JJ, Wang X, Paranal R, Wang H, Eum Y, Lin M, Haikala HM, Li J,

Xu Y, Alessi JV, Ch - hoeu C, Mira A, Patrucco E, Redig AJ, Köhler J, Richard E, Nokin MJ, Santamaria D, Gokhale PC, Awad MM, Jänne PA, Ambrogio C. Comparative analysis and isoform-specific therapeutic vulnerabilities of KRAS mutations in non-small cell lung cancer. Clinical Cancer Research, 2022 January.

Ultimo aggiornamento: 04/11/2024