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Molekularpathologie: Targeting KRAS-Mutant Tumors

Freitag, 17.04.2020

Dr. Ignacija Vlašić

Antrittsvorlesung von Dr. Ignacija Vlašić am 26. Mai um 17 Uhr s.t.

Die Antrittsvorlesung findet als Videokonferenz statt. Zugang: meetingsemea20.webex.com/meet/pr955054122

KRAS is one of the most frequently studied proto-oncogenes with mutations frequently occuring as a gain-of-function in lung, colorectal, pancreatic, endometrial, cervical, bladder, liver tumors and biliary tract malignancies. When turned on as a consequence of mutations, oncogenic KRAS transduces signals to its downstream effectors activating signaling pathways such as PI3K/AKT pathway or RAF/MEK/ERK (MAPK) pathway. This leads to upregulation of cell growth and proliferation which consequently drives carcinogenesis.

Due to high prevalence of KRAS-driven cancers, different strategies have been in use to target mutated KRAS. One approch was to indirectly target proteins involved in KRAS signaling activation by inhibiting regulators upstream or effectors downstream of KRAS, while another strategy focused on designing small molecule inhibitors that would directly target mutant KRAS. Another indirect strategy of targeting KRAS-driven tumors was to exploit the deficiencies in the Nucleotide Excision Repair (NER) pathway which is directly responsible for resolution of DNA adducts induced by platinum-based drugs which have been the cornerstone for treating KRAS-driven cancers for decades.

Although many potential KRAS inhibitors have been developed with the attempt to specifically target mutant KRAS, there is still no approved therapy for KRAS-mutant tumors. One of the reason why the design of small molecule KRAS inhibitors turned out to be challenging is specific molecular structure of the KRAS protein. However, recently, the inhibitors that covalently bind to cysteine residue of KRAS(G12C) mutant protein have been developed and are in the clinical trails giving hope that specific KRAS-mutant tumors could finally be druggable.

In her lecture Dr. Vlasic will give an overview of her own research on sensitizing KRAS-mutant tumors to chemotherapy using in vivo preclinical models of KRAS-driven lung adenocarcinoma as well as recent findings of targeting KRAS-driven solid tumors.

Dr. Ignacija Vlašić schließt mit der Antrittsvorlesung ihre Habilitation im Fachgebiet Pathologie / Molekularpathologie an der Universität zu Lübeck ab.


 

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