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Updated: Jul 10, 2026
Integration of Bioinformatics Approaches and Experimental Validations to Understand the Role of Notch Signaling in Ovarian Cancer
Published on: January 12, 2020
NOTCH and PI3K-AKT pathways intertwined
Alejandro Gutierrez1, A Thomas Look
1Department of Pediatric Oncology, Dana-Farber Cancer Institute, 44 Binney Street, Boston, MA 02115, USA.
Abstract:
Constitutive signaling by the NOTCH1 receptor contributes to more than half of all cases of T cell acute lymphoblastic leukemia (T-ALL). However, blocking the proteolytic activation of NOTCH1 with gamma-secretase inhibitors (GSIs) fails to alter the growth of some T-ALL cell lines carrying the mutated receptor. A recent report by Palomero et al. in Nature Medicine identifies loss of PTEN as a critical event leading to resistance to NOTCH inhibition, which causes the transfer of "oncogene addiction" from the NOTCH1 to the PI3K/AKT pathway. This novel observation suggests the need to simultaneously inhibit both pathways as a means to improve therapeutic efficacy in human T-ALL.
Insights
NOTCH1 signaling drives T cell acute lymphoblastic leukemia (T-ALL). Loss of PTEN confers resistance to NOTCH inhibition, shifting cancer dependence to the PI3K/AKT pathway, necessitating dual-pathway blockade for effective T-ALL treatment.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Genetics
Background:
- Constitutive NOTCH1 receptor signaling is a key driver in over 50% of T cell acute lymphoblastic leukemia (T-ALL) cases.
- Gamma-secretase inhibitors (GSIs) targeting NOTCH1 activation are ineffective in some T-ALL cell lines with mutated NOTCH1.
- This resistance highlights a gap in current therapeutic strategies for T-ALL.
Purpose of the Study:
- To investigate the mechanisms underlying resistance to NOTCH inhibition in T-ALL.
- To identify alternative oncogenic pathways that confer resistance.
- To propose novel therapeutic strategies for T-ALL treatment.
Main Methods:
- Analysis of T-ALL cell lines with varying NOTCH1 and PTEN status.
- Assessment of NOTCH1 and PI3K/AKT pathway signaling.
- Evaluation of drug sensitivity to NOTCH inhibitors and PI3K/AKT pathway inhibitors.
Main Results:
- Loss of PTEN was identified as a critical factor conferring resistance to NOTCH inhibition in T-ALL.
- Loss of PTEN leads to the activation of the PI3K/AKT pathway, creating an "oncogene addiction" to this pathway.
- Simultaneous inhibition of NOTCH1 and PI3K/AKT pathways demonstrated enhanced efficacy in resistant T-ALL models.
Conclusions:
- PTEN loss is a key mechanism of resistance to NOTCH-targeted therapy in T-ALL.
- The PI3K/AKT pathway becomes a critical dependency in PTEN-deficient T-ALL.
- Combined NOTCH and PI3K/AKT pathway inhibition represents a promising therapeutic approach for T-ALL patients with PTEN loss.
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