Dual targeting of RET and SRC synergizes in RET fusion-positive cancer cells

Area of Science:

• Oncology
• Molecular Biology
• Cancer Therapeutics

Background:

• Rearranged during transfection (RET) fusions are key drivers in non-small cell lung cancer (NSCLC) and papillary thyroid carcinoma (PTC).
• Resistance to selective RET tyrosine kinase inhibitors (TKIs) often arises from RET-independent bypass pathways, necessitating novel therapeutic strategies.
• Potential crosstalk between RET and proto-oncogene tyrosine-protein kinase SRC suggests a combined inhibition approach.

Purpose of the Study:

• To investigate the anticancer effects of combining SRC tyrosine kinase inhibitors (TKIs) with selective RET TKIs in RET fusion-positive (RET+) NSCLC and PTC.
• To elucidate the molecular mechanisms underlying the synergistic effects of combined RET and SRC inhibition.
• To evaluate the potential of SRC TKIs in overcoming resistance to existing RET-targeted therapies.

Main Methods:

• Utilized dasatinib, a multitargeted SRC TKI, in combination with RET TKIs in RET+ NSCLC and PTC cell lines.
• Employed genetic rescue experiments to confirm SRC dependency of combination effects.
• Conducted phosphoproteomics analysis and validated findings using selective inhibitors and small interfering RNAs (siRNAs) targeting key signaling molecules.

Main Results:

• Dasatinib significantly enhanced the efficacy of RET TKIs in RET+ NSCLC and PTC cells, demonstrating SRC-dependent synergy.
• The observed synergy was primarily mediated by the suppression of downstream serine/threonine-protein kinase PAK signaling, with contributions from AKT and ribosomal protein S6.
• A next-generation clinical SRC inhibitor, eCF506 (NXP900), also demonstrated synergistic effects, and SRC TKIs restored sensitivity in selpercatinib-resistant PTC cells.

Conclusions:

• Co-inhibition of RET and SRC signaling pathways demonstrates significant therapeutic potential in RET+ NSCLC and PTC.
• Targeting SRC, particularly with next-generation inhibitors, can overcome resistance mechanisms developed against selective RET TKIs.
• Combined SRC and RET inhibition represents a promising clinical strategy for both TKI-naïve and TKI-resistant RET-driven cancers.