Exploiting collateral sensitivity in the evolution of resistance to tyrosine kinase inhibitors in soft tissue...

Area of Science:

• Oncology
• Pharmacology
• Cancer Biology

Background:

• Broad-spectrum multi-target tyrosine kinase inhibitors (mTKIs) are approved for soft tissue sarcoma (STS) treatment.
• Acquired resistance to mTKIs is a significant clinical challenge, limiting durable treatment responses in STS patients.
• Novel strategies are needed to overcome mTKI resistance and improve therapeutic outcomes.

Purpose of the Study:

• To investigate resistance mechanisms in STS cells treated with mTKIs.
• To identify alternative therapeutic strategies to overcome acquired mTKI resistance.
• To explore the potential of collateral sensitivity for adaptive therapy in STS.

Main Methods:

• Evaluating cross-resistance patterns in STS cells upon acquisition of resistance to clinically relevant mTKIs.
• Investigating the development of collateral sensitivities during the acquisition of drug resistance.
• Assessing the efficacy of exploiting collateral sensitivity with alternative drugs, specifically sitravatinib and infigratinib, for adaptive therapy.

Main Results:

• STS cells acquiring resistance to one mTKI exhibit cross-resistance to others, and sequential treatment offers no delay in resistance.
• STS cells develop collateral sensitivities to alternative drugs as they acquire resistance to mTKIs.
• The mTKI sitravatinib rapidly induces collateral sensitivity to the FGFR inhibitor infigratinib, which effectively suppresses STS cell growth when used in an adaptive therapy approach.

Conclusions:

• Collateral sensitivity represents a promising strategy to overcome acquired resistance to mTKIs in STS.
• Adaptive therapy exploiting collateral sensitivity may offer a novel approach to achieve durable treatment responses in STS patients.
• Further clinical exploration of collateral sensitivity-based adaptive therapy is warranted for mTKI-resistant STS.