Screen for FDA-approved compounds that induce collateral sensitivity in multidrug resistant cancer

Wednesday, October 10, 2012 — Poster Session II
Noon – 2:00 p.m	Natcher Conference Center, Building 45	NCI	CANCER-18

Authors

• A.D.T Kwit
• M.D. Hall
• K.R. Brimacombe
• M. Shen
• M.B. Boxer
• M.M. Gottesman

Abstract

Cancer multidrug resistance (MDR), the simultaneous resistance to structurally and mechanistically dissimilar chemotherapeutics, has long been a challenge to resolve clinically. A major mechanism of cancer cell resistance is the expression of the energy-dependent efflux pump P-glycoprotein (P-gp, MDR1, ABCB1). Preventing chemotherapeutics from entering cells, expression of this multidrug pump contributes to approximately half of human cancer resistance and is correlated with poor prognosis. While it was believed drugs that induce collateral sensitivity (CS), the selective killing of MDR cells over their parental cell line, would be an excellent solution to this resistance problem, the few drug candidates identified have not been ideal for clinical use. In order to identify better CS-inducing drugs, a high-throughput screen (HTS) was performed on a vinblastine-selected MDR adenocarcinoma cell line using the NCGC Pharmaceutical Collection (NPC). Of the 3,286 compounds tested, 28 validated leads were identified, and PDE3 inhibitor anagrelide was found to be the most active. This poster reports the results of the NPC HTS.

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