Functional Investigation of IGF1R Mutations in Multiple Myeloma

Area of Science:

• Oncology
• Molecular Biology
• Genetics

Background:

• High expression and mutations of insulin-like growth factor-1 receptor (IGF1R) are linked to worse prognosis in multiple myeloma (MM).
• Previous trials combining an IGF1R inhibitor with bortezomib showed promise, but IGF1R expression didn't correlate with response.

Purpose of the Study:

• To investigate the functional impact of IGF1R mutations on survival signaling, cell viability, proliferation, and response to therapy in MM.
• To evaluate the anti-myeloma activity of linsitinib, an IGF1R inhibitor, in combination with carfilzomib, a proteasome inhibitor.

Main Methods:

• Transfected human myeloma cell lines (HMCLs) with wild-type (WT) and mutant IGF1R.
• Generated CRISPR-Cas9 IGF1R knockouts in HMCLs.
• Tested the anti-MM activity of linsitinib alone and with carfilzomib in seven HMCLs.

Main Results:

• IGF1R knockout reduced cell proliferation.
• IGF1R overexpression moderately increased survival signaling but did not affect viability.
• The mutant IGF1R (D1146N) affected IGF1R activation but not downstream signaling.
• Linsitinib and carfilzomib combination demonstrated enhanced anti-myeloma activity in most tested HMCLs, irrespective of IGF1R mutation status.

Conclusions:

• IGF1R mutations can influence IGF1R activation and downstream signaling pathways.
• Combining linsitinib with carfilzomib represents a potential therapeutic strategy for MM patients who may benefit from IGF1R blockade.