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ALCAM regulates multiple myeloma chemoresistant side population

Fangfang Wang1, Zhang Dan1, Hongmei Luo1

  • 1Department of Hematology, West China Hospital/State Key Laboratory of Biotherapy and Cancer Center, Sichuan University, Chengdu, China.

Cell Death & Disease
|February 11, 2022
PubMed

Insights

Activated Leukocyte Cell Adhesion Molecule (ALCAM) inhibits multiple myeloma (MM) drug resistance by regulating the side population (SP) of cells. Targeting the Epidermal Growth Factor Receptor (EGFR) may enhance MM treatment efficacy.

Area of Science:

  • Oncology
  • Cell Biology
  • Molecular Medicine

Background:

  • Drug resistance remains a significant barrier to curing multiple myeloma (MM).
  • Activated Leukocyte Cell Adhesion Molecule (ALCAM) has been identified as a prognostic factor in MM.
  • ALCAM was previously shown to inhibit Epidermal Growth Factor (EGF)/Epidermal Growth Factor Receptor (EGFR)-initiated MM clonogenicity.

Purpose of the Study:

  • To investigate the role of the ALCAM-EGF/EGFR axis in mediating drug resistance in MM.
  • To elucidate the mechanisms by which ALCAM influences the drug-resistant side population (SP) in MM.
  • To evaluate the therapeutic potential of targeting the EGFR pathway in MM.

Main Methods:

  • Investigated the ratio of SP cells in ALCAM-knockdown MM cells under various conditions (BMSCs, EGF).
  • Assessed the drug resistance of SP MM cells to melphalan and bortezomib.
  • Examined the effect of EGFR activation and ALCAM on the hedgehog pathway and SP-genesis.
  • Analyzed mitochondrial function in SP MM cells and its role in SP-genesis.
  • Conducted animal studies using combination therapy with an anti-MM agent and gefitinib.

Main Results:

  • ALCAM knockdown increased the SP cell ratio in MM, particularly with bone marrow stromal cells or EGF.
  • SP MM cells demonstrated resistance to melphalan and bortezomib, and drug treatment promoted SP-genesis.
  • EGFR activation, stimulated by EGF, promoted SP ratio via the hedgehog pathway, while ALCAM inhibited pro-MM cell signaling.
  • SP MM cells had increased mitochondria, and interfering with mitochondrial function inhibited SP-genesis.
  • Combination therapy with an anti-MM agent and gefitinib prolonged survival in MM-bearing mice.

Conclusions:

  • ALCAM acts as a novel negative regulator of drug resistance in multiple myeloma.
  • The ALCAM-EGF/EGFR signaling axis is crucial in regulating MM drug resistance via the SP.
  • EGFR inhibitors, such as gefitinib, represent a promising therapeutic strategy to improve MM treatment outcomes.

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