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Activation of the MAPK pathway mediates resistance to PI3K inhibitors in chronic lymphocytic leukemia

Ishwarya Murali1,2, Siddha Kasar1,2, Aishath Naeem1,2

  • 1Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA.

Blood
|March 8, 2021
PubMed

Insights

Activating mutations in MAP2K1, BRAF, and KRAS drive resistance to phosphatidylinositol 3-kinase delta (PI3Kδ) inhibitors in chronic lymphocytic leukemia (CLL). Combining PI3Kδ and ERK inhibitors may overcome this resistance.

Area of Science:

  • Oncology
  • Hematology
  • Molecular Biology

Background:

  • Bruton tyrosine kinase (BTK) and phosphatidylinositol 3-kinase delta (PI3Kδ) inhibitors targeting the B-cell receptor (BCR) pathway have transformed chronic lymphocytic leukemia (CLL) treatment.
  • Mechanisms of resistance to PI3Kδ inhibitors in CLL are not well understood, unlike resistance to BTK inhibitors.

Purpose of the Study:

  • To investigate the mechanisms of resistance to PI3Kδ inhibitors in patients with multiply relapsed CLL.
  • To identify genetic mutations associated with non-response to PI3Kδ inhibitor therapy.

Main Methods:

  • Longitudinal whole-exome sequencing of cells from 28 patients with multiply relapsed CLL treated with PI3K inhibitors.
  • In vitro studies involving overexpression of MAP2K1 mutants to assess their impact on ERK phosphorylation and drug resistance.

Main Results:

  • Sixty percent of nonresponder patients had baseline activating mutations in MAP2K1, BRAF, and KRAS.
  • PI3Kδ inhibition did not suppress ERK phosphorylation (pERK) in nonresponder CLL cells, irrespective of mutations.
  • MEK inhibitor treatment restored ERK inhibition, and MAP2K1 mutants increased basal and inducible pERK, conferring resistance to idelalisib.

Conclusions:

  • MAPK/ERK pathway activation is a key mechanism of resistance to PI3Kδ inhibitors in CLL.
  • Combination therapy with PI3Kδ and ERK inhibitors is a potential strategy to overcome resistance in CLL patients.

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