Targeting the Protein Kinase Α Pathway to Overcome Chemotherapy Resistance in AML

Acute myeloid Leukemia (AML) is the most common form of acute leukemia in adults. Each year over 20,000 adults will be diagnosed with AML in the United States and almost 70% will perish within 5 years of diagnosis, frequently due to relapsed disease. AML is primarily treated with intensive chemotherapy using DNA-damaging agents such as cytarabine (AraC) and daunorubicin. In many cases, however, AML is either refractory to chemotherapy treatment or initially responsive but resistant at relapse. Therefore, developing new strategies for eradicating chemotherapy-resistant disease is vital to improving outcomes for AML patients. Previous data from our group have shown that low expression of the DNA damage response gene Schlafen 11 (SLFN11) correlates with lower overall survival in AML patients and predicts resistance to AraC in TP53-mutated AML cell lines (Small et al, Blood Neoplasia, accepted 07/2024). We have expanded upon this work using a genetically diverse panel of human AML cell lines (including wild-type TP53 cell lines) and observed that the expression of SLFN11 negatively correlated with response to the DNA damaging agents AraC and daunorubicin. This correlation was not observed using other AML-directed drugs such as venetoclax or azacitidine, further corroborating previous data from our group. Additionally, the expression of SLFN11 and the DNA damage drug response were independent of the diverse genetic mutations present in these cell lines, suggesting SLFN11 expression is an independent variable that determines sensitivity to these drugs. To find novel targets for SLFN11-deficient cells, RNA sequencing was performed on SLFN11 knockout cells developed in the human monocytic AML cell line, U937. We observed that the protein kinase A (PKA) pathway genes AKAP7 and PDE7B were upregulated in SLFN11 knockout cells compared to control cells. We then combined PKA pathway modulation with DNA damage induction to test whether this strategy could restore sensitivity to chemotherapeutics in SLFN11-deficient cells. We found that targeting the PKA pathway using the PDE7-specific inhibitor BRL-50481 partially restored sensitivity to AraC in the SLFN11 knockout cells, without further sensitizing the parental cell line. This study expands upon the role of SLFN11 as a novel biomarker in AML for predicting patient response to DNA-damaging agents. It also demonstrates that alternative treatment strategies, such as combining AraC and PKA pathway inhibitors, may be a viable treatment option in SLFN11-deficient AML patients.

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