Novel Human-Derived <i>RET</i> Fusion NSCLC Cell Lines Have Heterogeneous Responses to RET Inhibitors and Differential Regulation of Downstream Signaling

Rearranged during transfection (RET) rearrangements occur in 1% to 2% of lung adenocarcinomas as well other malignancies and are now established targets for tyrosine kinase inhibitors. We developed three novel RET fusion–positive (RET+) patient–derived cancer cell lines, CUTO22 [kinesin 5B (KIF5B)–RET fusion], CUTO32 (KIF5B-RET fusion), CUTO42 (echinoderm microtubule-associated protein-like 4–RET study RET signaling response therapy. confirmed each our lines expresses the fusion protein assessed their sensitivity found that were sensitive multiple inhibitors, whereas line was &gt;10-fold more resistant discovered RET+ had differential regulation mitogen-activated phosphoinositide 3-kinase/protein B (AKT) pathways. After inhibition RET, cells robust phosphorylated AKT (pAKT), sustained activation. Next, we performed a drug screen, which revealed (&lt;1 nM IC50) two cycle–regulating proteins, polo-like 1 Aurora A. Finally, show these CUTO42, successfully establish xenografted tumors nude mice. demonstrated inhibitor BLU-667 effective at inhibiting tumor growth but much less profound effect tumors, consistent with vitro experiments. These data highlight utility new RET+ models elucidate differences inhibitors downstream regulation. Our effectively recapitulate interpatient heterogeneity observed reveal opportunities alternative or combination therapies. SIGNIFICANCE STATEMENT have derived characterized rearranged (RET) non-small they responses signaling, an area has previously been limited by lack diverse modes endogenous fusions. offer important insight into potential therapeutic targets.