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Keppler Lab - Research

SAMHD1-dependent chemoresistance and approaches to overcome it

Nucleoside analogs frequently constitute the backbone of chemotherapy regimens in malignant diseases, however success is variable and often unpredictable. The identification of biomarkers to guide treatment decisions as well as novel therapeutic interventions to overcome chemoresistance are urgently needed. Together with the group of Prof. Jindrich Cinatl in Frankfurt we discovered that expression of SAMHD1 hydrolyzes and thus inactivates important metabolites of several of these nucleoside analogs, including cytarabine, and, importantly, predictes therapeutic success in patients with acute myeloid leukemia (AML) (Schneider et al., Nature Medicine 2017; Oellerich et al., Nature Communications 2019).

More recent studies elucidated the impact of SAMHD1 on other chemotherapeutics (Rothenburger et al., Communications Biology 2020) and differences in intrinsic and acquired drug resistance (Rothenburger et al., Journal of Experimental & Clinical Cancer Research 2021).

Our major goals are to

  1. explore the breadth of this specific mode of chemoresistance in other hematological and solid tumors,
  2. to advance different strategies to target SAMHD1 and
  3. gain molecular understanding for SAMHD1’s biological functions in physiology and cancer.
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