ATR addiction in multiple myeloma: synthetic lethal approaches exploiting established therapies

Area of Science:

• Oncology
• Cancer Therapeutics
• DNA Damage Response

Background:

• PARP inhibitors are effective for BRCA1/2-mutated cancers by targeting DNA damage response.
• Synthetic lethality mechanisms are sought for hematological cancers like multiple myeloma.
• Established treatments for multiple myeloma include melphalan and doxorubicin.

Purpose of the Study:

• To identify synthetic lethality mechanisms in multiple myeloma analogous to PARP inhibition in other cancers.
• To evaluate the combination of ATR inhibition (VX-970) with melphalan in multiple myeloma models.
• To investigate the role of ATM inhibition in combination with doxorubicin for multiple myeloma treatment.

Main Methods:

• In vitro, ex vivo, and in vivo studies were conducted using multiple myeloma cell lines and patient cells.
• Assessed were cell proliferation, apoptosis induction, tumor growth, and animal survival.
• Tested combinations included ATR inhibition (VX-970) with melphalan, and ATM inhibition with doxorubicin.

Main Results:

• ATR inhibition demonstrated strong synergy with melphalan, significantly reducing proliferation and inducing apoptosis in myeloma cells, including resistant ones.
• The combination therapy markedly reduced tumor burden and prolonged survival in animal models.
• ATM inhibition showed only marginal effects on myeloma cell survival, even with doxorubicin.

Conclusions:

• Multiple myeloma cells are highly dependent on ATR, but not ATM, for DNA repair.
• Combining ATR inhibitors like VX-970 with existing therapies offers a potentially broad benefit for multiple myeloma patients.
• This strategy represents a promising new therapeutic avenue for multiple myeloma treatment.