Targeting NOTCH3 to eradicate dormant and therapy-resistant multiple myeloma cells.

Area of Science:

• Oncology
• Cancer Biology
• Immunology

Background:

• Multiple myeloma (MM) is often incurable due to tumor relapse.
• Clonal heterogeneity and dormant cells contribute to therapy resistance and relapse in MM.
• Eliminating diverse resistant cell populations within the tumor niche is a clinical challenge.

Purpose of the Study:

• To identify shared survival mechanisms in drug-resistant proliferating and dormant multiple myeloma cells.
• To explore therapeutic strategies targeting these common vulnerabilities for simultaneous elimination of distinct tumor-repopulating clones.

Main Methods:

• Analysis of clinical databases and drug-resistant myeloma cell lines.
• Pharmacologic targeting of identified common resistance mechanisms.
• Assessment of therapeutic impact in preclinical mouse models with resistant and dormant cells.

Main Results:

• Upregulation of Notch signaling pathway components was observed in dormant and drug-resistant MM cells, correlating with poor outcomes.
• Selective NOTCH3 blockade or pan-Notch inhibition reduced tumor burden in preclinical models.
• Coexisting dormant and bortezomib-resistant cells were eliminated by Notch inhibition.

Conclusions:

• NOTCH3-dependent survival programs are a shared vulnerability in therapy-refractory and dormant MM cells.
• Targeting these Notch pathways can overcome diverse cancer cell evasion mechanisms.
• This strategy holds potential for preventing MM relapse and prolonging remission.