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Resistance mechanism to Notch inhibition and combination therapy in human T-cell acute lymphoblastic leukemia

Linlin Cao1, Gustavo A Ruiz Buendía2, Nadine Fournier1,2

  • 1Ecole Polytechnique Fédérale de Lausanne, School of Life Sciences, Swiss Institute for Experimental Cancer Research, Swiss Cancer Center Leman, Lausanne, Switzerland.

Blood Advances
|June 26, 2023
PubMed

Insights

Loss of PIK3R1 confers resistance to NOTCH inhibitors in T-cell acute lymphoblastic leukemia (T-ALL). Combining NOTCH and CDK4/6 inhibitors offers a potent therapeutic strategy against T-ALL.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Gain-of-function mutations in NOTCH1 are common in T-cell acute lymphoblastic leukemia (T-ALL).
  • The Notch signaling pathway is a key therapeutic target for T-ALL.
  • Tumor heterogeneity and acquired resistance limit the efficacy of targeted therapies, leading to relapse.

Purpose of the Study:

  • To identify resistance mechanisms to NOTCH inhibitors in T-ALL.
  • To discover novel combination therapies for combating T-ALL.

Main Methods:

  • Genome-wide CRISPR-Cas9 screening was employed to identify resistance genes.
  • Investigated the role of phosphoinositide-3-kinase regulatory subunit 1 (PIK3R1) loss in NOTCH inhibitor resistance.
  • Evaluated therapeutic combinations in T-ALL xenotransplantation models.

Main Results:

  • Mutational loss of PIK3R1 was identified as a mechanism conferring resistance to NOTCH inhibition.
  • PIK3R1 deficiency enhances PI3K/AKT signaling, impacting cell cycle and spliceosome machinery.
  • Simultaneous targeting of cyclin-dependent kinases 4 and 6 (CDK4/6) and NOTCH demonstrated significant efficacy.

Conclusions:

  • PIK3R1 loss is a key resistance mechanism to NOTCH-targeted therapy in T-ALL.
  • Targeting PI3K/AKT signaling downstream of NOTCH is crucial for overcoming resistance.
  • Combination therapy with NOTCH and CDK4/6 inhibitors presents a promising strategy for T-ALL treatment.

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