FMS-like tyrosine kinase 3 (FLT3) modulates key enzymes of nucleotide metabolism implicated in cytarabine responsiveness in pediatric acute leukemia.

Treatment of pediatric acute leukemia might involve combined therapies targeting the FMS-like tyrosine kinase 3 (FLT3) receptor (i.e. quizartinib - AC220) and nucleotide metabolism (cytarabine - AraC). This study addressed the possibility of FLT3 modulating nucleoside salvage processes and, eventually, cytarabine action. Bone marrow samples from 108 pediatric leukemia patients (B-cell precursor acute lymphoblastic leukemia, BCP-ALL: 83; T-ALL: 9; acute myeloid leukemia, AML: 16) were used to determine the mRNA expression levels of FLT3, the cytarabine activating kinase dCK, and the nucleotidases cN-II and SAMHD1. FLT3 mRNA levels positively correlated with dCK, cN-II and SAMHD1 in the studied cohort. FLT3 inhibition using AC220 promoted the expression of cN-II in MV4-11 cells. Indeed, inhibition of cN-II with anthraquinone-2,6-disulfonic acid (AdiS) further potentiated the synergistic action of AC220 and cytarabine, at low concentrations of this nucleoside analog. FLT3 inhibition also down-regulated phosphorylated forms of SAMHD1 in MV4-11 and SEM cells. Thus, inhibition of FLT3 may also target the biochemical machinery associated with nucleoside salvage, which may modulate the ability of nucleoside-derived drugs. In summary, this contribution highlights the need to expand current knowledge on the mechanistic events linking tyrosine-kinase receptors, likely to be druggable in cancer treatment, and nucleotide metabolism, particularly considering tumor cells undergo profound metabolic reprogramming.

Challenges in precision medicine in pancreatic cancer: A focus in cancer stem cells and microbiota.

Pancreatic cancer adenocarcinoma (PDAC) is a lethal disease, with the lowest 5-years survival rate of all cancers due to late diagnosis. Despite the advance and success of precision oncology in gastrointestinal cancers, the frequency of molecular-informed therapy decisions in PDAC is currently neglectable. The reasons for this dismal situation are mainly the absence of effective early diagnostic biomarkers and therapy resistance. PDAC cancer stem cells (PDAC-SC), which are regarded as essential for tumor initiation, relapse and drug resistance, are highly dependent on their niche i.e. microanatomical structures of the tumor microenvironment. There is an altered microbiome in PDAC patients embedded within the highly desmoplastic tumor microenvironment, which is known to determine therapeutic responses and affecting survival in PDAC patients. We consider that understanding the communication network that exists between the microbiome and the PDAC-SC niche by co-culture of patient-derived organoids (PDOs) with TME microbiota would recapitulate the complexity of PDAC paving the way towards a precision oncology treatment-response prediction.

GDF15 and ACE2 stratify COVID-19 patients according to severity while ACE2 mutations increase infection susceptibility.

Coronavirus disease 19 (COVID-19) is a persistent global pandemic with a very heterogeneous disease presentation ranging from a mild disease to dismal prognosis. Early detection of sensitivity and severity of COVID-19 is essential for the development of new treatments. In the present study, we measured the levels of circulating growth differentiation factor 15 (GDF15) and angiotensin-converting enzyme 2 (ACE2) in plasma of severity-stratified COVID-19 patients and uninfected control patients and characterized the in vitro effects and cohort frequency of ACE2 SNPs. Our results show that while circulating GDF15 and ACE2 stratify COVID-19 patients according to disease severity, ACE2 missense SNPs constitute a risk factor linked to infection susceptibility.