Loss of oncogenic Notch1 with resistance to a PI3K inhibitor in T-cell leukaemia

Abstract

Mutations that deregulate Notch1 and Ras/PI3 kinase/Akt signalling are prevalent in T lineage acute lymphoblastic leukaemia (T-ALL), and often coexist. The PI3 kinase inhibitor GDC-0941 was active against primary T-ALLs from wild-type and KrasG12D mice and addition of the MEK inhibitor PD0325901 increased efficacy. Mice invariably relapsed after treatment with drug resistant clones, most of which unexpectedly had reduced levels of activated Notch1 protein, down-regulated many Notch1 target genes, and exhibited cross-resistance to γ secretase inhibitors. Multiple resistant primary T-ALLs that emerged in vivo did not contain somatic Notch1 mutations present in the parental leukaemia. Importantly, resistant clones up-regulated PI3K signalling. Consistent with these data, inhibiting Notch1 activated the PI3K pathway, providing a likely mechanism for selection against oncogenic Notch1 signalling. These studies validate PI3K as a therapeutic target in T-ALL and raise the unexpected possibility that dual inhibition of PI3K and Notch1 signalling could facilitate drug resistance in T-ALL.

Up-regulated A20 promotes proliferation, regulates cell cycle progression and induces chemotherapy resistance of acute lymphoblastic leukemia cells

“…However, the mechanisms leading to uncontrolled cell proliferation in these patients remain elusive. Multiple molecular dysfunctions associated with ALL leukemogenesis may enhance tumor growth and chemotherapy resistance, and these have been attributed to Notch1, MDM2, p53 and microRNAs [17][18][19][20]. Considerable effort has been made to improve our understanding of the pathogenesis of ALL so that we can better treat these patients.…”

Preclinical efficacy of MEK inhibition in Nras-mutant AML

“…Despite this, combined GDC-0941/PD901 was highly effective in MOL4070LTR-induced Kras-mutant T-cell acute lymphoblastic leukemia, inducing prolonged survival, clonal evolution, and phenotypic drug resistance. 34 Furthermore, the single-agent efficacy of PD901 in Nras G12D AML was less pronounced than in Nf1-mutant AML, 24 adding further evidence that targeting the aberrant signaling output of hyperactive Ras is highly isoform and context dependent.…”

“…34 The toxicity observed with combined MAPK and PI3K/Akt inhibition suggests that investigating isoformspecific PI3K inhibitors may be of value. Despite this, combined GDC-0941/PD901 was highly effective in MOL4070LTR-induced Kras-mutant T-cell acute lymphoblastic leukemia, inducing prolonged survival, clonal evolution, and phenotypic drug resistance.…”

“…PD901 and GDC-0941 were administered at the maximum tolerated doses previously established in this strain background (F1 C57BL/6 3 129Sv/Jae). 24,[32][33][34] Leukemias #6730 and #8064 are classified as transplantable MPNs 35 because recipient mice develop progressive leukocytosis, retain residual erythropoiesis, and have a median survival of 70 days (supplemental Figure 3A-B). These MPNs represent a more aggressive disease than the indolent MPNs developed in Nras-mutant mice without retroviral insertions that are not transplantable to sublethally irradiated recipients.…”

The relevance of PTEN-AKT in relation to NOTCH1-directed treatment strategies in T-cell acute lymphoblastic leukemia

“…61 Additionally, T-ALL induced by retroviral insertional mutagenesis in wild-type or RasG12D-mutant mice demonstrated an initial response to PI3K-inhibitor GDC-0941 treatment. 62 However, this treatment led to the survival and outgrowth of drug-resistant clones with active PI3K-AKT signaling that frequently had reduced Notch1 signaling. 62 To avoid resistance when combined with NOTCH1 inhibitors, the authors propose a sequential treatment using a NOTCH1 inhibitor at diagnosis to eliminate NOTCH1 mutant clones followed by PI3K/AKT inhibitor treatment.…”