T cell acute lymphoblastic leukemia (T-ALL) is an aggressive cancer for which current therapies are toxic and frequently ineffective. Mutations that activate the Notch1 and Ras/PI3K/Akt signaling pathways are common in T-ALL and often coexist. Thus, inhibiting these pathways alone and in combination is a rational therapeutic strategy. Notch1 inhibition with a gamma-secretase inhibitor (GSI) was recently evaluated in patients with disappointing results. PI3K inhibitors are just entering Phase I clinical trials. GDC-0941 is a potent PI3K inhibitor that is currently advancing in clinical development that we evaluated for efficacy and mechanisms of drug resistance both in cell lines and primary murine T-ALLs. Cell lines are uniformly sensitive to GDC-0941, however gradual dose escalation results in resistant lines. In vivo, GDC-0941 is active against primary T-ALLs, but treated mice invariably relapse with drug resistant clones. Unexpectedly, a majority of GDC-0941-resistant cell lines and primary leukemias showed reduced levels of activated Notch1 protein, down-regulate many Notch1 target genes, and display cross-resistance to γ secretase inhibitors (GSIs). In multiple cases, Notch1 mutations that were present at enrollment were absent at relapse. Importantly, resistant clones that emerge both in vitro and in vivo up-regulate PI3K signaling indicating an “on pathway” mechanism of resistance. Consistent with these data, inhibition of Notch1 signaling promotes GDC-0941 resistance and enhances PI3K signaling, whereas expression of activated Notch1 increases the GDC-0941 sensitivity of mouse and human T-ALL cell lines. Thus, oncogenic Notch1 mutations that promote clonal outgrowth during malignant transformation unexpectedly undergo negative selection during treatment with GDC-0941. These studies validate PI3K as an important therapeutic target in T-ALL and raise the unexpected possibility that administering Notch1 and PI3K inhibitors in combination will accelerate drug resistance.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):PR08.
Citation Format: Monique Dail. Loss of oncogenic Notch1 signaling contributes to PI3 kinase inhibitor resistance in T lineage leukemia. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr PR08.
- Copyright © November 2013, American Association for Cancer Research