NF1 (neurofibromatosis 1) controls microtubule dynamics and dictates sensitivity to maytansinoids (AACR 2023)
We showed that multiple CRISPR-Cas9-engineeerd NF1 KO HER2+ breast cancer cells (BT-474, SK-BR3, HCC1954) become exquisitely sensitive to the Antibody-Drug Conjugate (ADC) Trastuzumab emtansine (T-DM1); we here investigate the underlying mechanism.TDM1 hypersensitivy was specific to the maytansin microtubule-targeting payload, since it was i) replicated by the naked payload but not the naked antibody; ii) absent with other ADCs (T-DxD); iii) not accompanied by increased TDM1 uptake; iv) associated with increased tubulin-maytansin binding in KO cells, as per Cellular Thermal Shift Assay. By IF on cocultured WT/KO live cells, KO cells showed significantly higher GTP-tubulin, known to cause microtubular hyperstability, suggesting the intriguing possibility that NF1 may directly regulate tubulin intrinsic GTP-hydrolyzing activity, similar to its role on RAS. In conclusion, we provide extensive mechanistic evidence for a direct and previously underappreciated role of NF1 in microtubular dynamics, which reshapes our understanding of its tumor-suppressive activity and provides a rationale for pharmacological targeting of NF1-mutated tumors.