Dual checkpoint blockade for the treatment of KRAS- or BRAF-driven neoplastic disease

• Applicant: Professor Dr. Christian Reinhardt
• Subject Area: Hematology, Oncology
• Term: from 2016 to 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 289354784

KRAS is one of the most frequently mutated genes in human cancer. As direct targeting of KRAS is difficult, indirect approaches have been proposed. These regimens have shown promising preclinical activity and multiple clinical trials are underway, but the clinical feasibility and validity has yet to be demonstrated.Our own preliminary data show that KRAS-driven tumors display a non-oncogene addiction to functional cell cycle checkpoint signaling through Chk1 and MK2. Our approach thus substantially differs from most previous strategies, developed to treat KRAS-mutant cancers, which typically target KRAS or one of its direct downstream signaling effectors, in order to abolish its oncogenic potential. However, many questions regarding this novel synthetic lethal interaction remain unanswered and currently preclude further validation in the clinic. For instance: Are other checkpoint kinases, such as ATM or Chk2 equally good targets for checkpoint-abrogating therapeutic regimens? This question is particularly important, as Chk1 knockout mice display embryonic lethality, which might suggest that long-term treatment with Chk1 inhibitors might be limited by toxicity. Do other KRAS- or BRAF-driven malignancies, such as colorectal cancer display similar sensitivity against Chk1- and MK2-inhibitors? Could immuno-histochemistry-based biomarkers be established that allow an accurate prediction of cell cycle checkpoint dependence? To address these questions and to facilitate a clinical translation of our novel treatment regimen, we propose three specific aims in this application:Aim 1: Validate oncogenic KRAS and BRAF mutations as predictors for non-oncogene addiction to cell cycle checkpoint signalingAim 2: Assess whether Chk2- or ATM-inhibitors are equally effective combination partners as Chk1-inhibitorsAim 3: Establish immunohistochemistry-based biomarkers to predict non-oncogene addiction to cell cycle checkpoint signalingThese aims specifically test the hypothesis that 1) KRAS and BRAF are generalizable predictors of cell cycle checkpoint addiction, independent of the cancer entity, 2) ATM- and Chk2 kinase inhibitors can substitute Chk1 inhibitors in the cell cycle checkpoint-abrogation regimen and 3) that in addition to DNA sequencing-based response prediction, immunohistochemistry-based scoring systems can be established that accurately predict response to cell cycle checkpoint-abrogating therapeutic regimens. Answering these questions in relevant, autochthonous mouse models and human material will pave the way for a rapid clinical validation of our hypothesis.

• DFG Programme: Research Grants