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Targeting the PI3K pathway in myeloproliferative neoplasms

Aaron T Gerds1, Niccolo Bartalucci2, Albert Assad3

  • 1Cleveland Clinic Taussig Cancer Institute Cleveland, Cleveland, OH, USA.

Expert Review of Anticancer Therapy
|June 28, 2022
PubMed
Abstract

Insights

Janus kinase (JAK) inhibitors are less effective over time for myeloproliferative neoplasms (MPNs). Combining JAK inhibitors with phosphatidylinositol-3 kinase (PI3K) inhibitors like parsaclisib may improve treatment outcomes for MPN patients.

Area of Science:

  • Hematology
  • Oncology
  • Molecular Biology

Background:

  • Myeloproliferative neoplasms (MPNs), particularly myelofibrosis, present challenges with decreasing Janus kinase (JAK) inhibitor efficacy and initial suboptimal responses.
  • Understanding the complex signaling pathways in MPNs is crucial for identifying new therapeutic targets and strategies.
  • The phosphatidylinositol-3 kinase (PI3K) pathway is implicated in MPN progression and resistance to JAK inhibition.

Purpose of the Study:

  • To discuss the role of PI3K in MPN pathogenesis and treatment resistance.
  • To explore the potential of targeting the PI3K pathway, specifically PI3Kδ, in combination with JAK/STAT pathway inhibition.
  • To evaluate the clinical potential of combining parsaclisib (a PI3Kδ inhibitor) with ruxolitinib for MPN treatment.

Main Methods:

  • Review of underlying mechanisms of MPN pathogenesis and treatment resistance.
  • Analysis of the role of PI3K pathway signaling in response to JAK inhibitors.
  • Consideration of initial clinical study results for combination therapies.

Main Results:

  • PI3K plays a significant role downstream of JAK signaling in promoting tumor cell proliferation.
  • PI3Kδ is particularly important in hematologic malignancies.
  • Concurrent targeting of PI3K and JAK/STAT pathways may enhance therapeutic efficacy.

Conclusions:

  • The combination of parsaclisib and ruxolitinib shows significant clinical potential for treating MPNs.
  • This combination may overcome resistance to JAK inhibitors and improve patient outcomes.
  • Further clinical trials are needed to confirm the efficacy and safety of parsaclisib in MPN treatment.
Keywords:
Combination therapyJAKPI3Kmyelofibrosisparsaclisibruxolitinib

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