KIT inhibitors

Oncogenic mutations leading to persistent kinase activities are associated with malignancies. Therefore, deciphering the signaling networks downstream these oncogenic stimuli remains a challenge to gather insights into targeted therapy.

Resistance to Kit inhibitors

Cell survival is driven by the Kit/Shp2/Ras/Mek/Erk1/2 pathway whereas G1/S transition during cell-cycle is accelerated by both the Kit/Stat5 and Kit/PI3K/Akt pathways.

The combined use of clinically relevant drugs, NVP-BEZ235 targeting cell cycle and Obatoclax targeting survival, demonstrated synergistic effects to inhibit leukemia cell growth.

This synergy was confirmed with a human mast leukemia cell line (HMC-1.2) that express mutant Kit.

Starting from LC-MS/MS analysis, elucidation of signaling networks downstream of oncogenic kinases provides a molecular rationale for pathway-targeted therapy to treat cancer cell refractory to Tyrosine Kinase inhibitors.

References

 Cotargeting signaling pathways driving survival and cell cycle circumvents resistance to Kit inhibitors in leukemia. Buet D, Gallais I, Lauret E, Denis N, Lombard B, Guillonneau F, Kosmider O, Loew D, Dusanter-Fourt I, Guillouf C, Mayeux P, Moreau-Gachelin F. Blood. 2012 Mar 22. PMID: 22438255