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Targeting the PREX2/RAC1/PI3Kβ Signaling Axis Confers Sensitivity to Clinically Relevant Therapeutic Approaches in

Catriona A Ford1, Dana Koludrovic1, Patricia P Centeno1

  • 1Cancer Research UK Scotland Institute, Glasgow, United Kingdom.

Cancer Research
|December 5, 2024
PubMed

Insights

Targeting the PREX2/RAC1/PI3Kβ pathway alongside MAPK therapies shows promise for treating BRAF-mutant melanoma. This combination strategy effectively overcomes resistance and improves outcomes in metastatic melanoma.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Metastatic melanoma presents significant clinical challenges, often developing resistance to BRAF-targeted therapies due to mutations like those in RAC1.
  • The RAC1-GTPase pathway, involving PREX2 and PI3Kβ, is implicated in melanoma progression and therapeutic resistance.

Purpose of the Study:

  • To investigate the role of PREX2 in melanoma development and its impact on therapeutic response.
  • To explore the potential of targeting the PREX2/RAC1/PI3Kβ axis to overcome resistance in BRAF-mutant melanoma.

Main Methods:

  • Utilized genetically engineered mouse models of melanoma.
  • Employed patient-derived BRAFV600E-driven melanoma cell lines.
  • Investigated the effects of genetic and pharmacologic inhibition of PREX2 and PI3Kβ.

Main Results:

  • PREX2 is not essential for melanoma initiation or progression but its absence sensitizes melanoma to MAPK pathway inhibitors.
  • Targeting PI3Kβ genetically or pharmacologically mimics PREX2 deficiency, enhancing sensitivity to therapy.
  • Combined targeting of MAPK and the PREX2/RAC1/PI3Kβ axis demonstrates superior efficacy over monotherapy in BRAF-mutant melanoma models.

Conclusions:

  • A druggable signaling axis involving PREX2, RAC1, and PI3Kβ exists in BRAF-mutant melanoma.
  • Combination therapy targeting both MAPK and the PREX2/RAC1/PI3Kβ pathway offers a potent strategy for treating metastatic melanoma and overcoming therapeutic resistance.

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