1. Drugging Drug Resistance
Jan-Hermen Dannenberg, Anton Berns 
Cell 
Volume 141, Issue 1, Pages (April 2010)
DOI: /j.cell
Copyright © 2010 Elsevier Inc. Terms and Conditions

2. Figure 1 Drug Resistance in Lung Tumor Cells
A population of non-small cell lung tumor cells (PC9 parental cancer cell line), carrying the activating mutation EGFRdel19, consists of a heterogeneous mix of drug-sensitive cells (blue), nongenetic, drug-tolerant persisters (DTP, red), and possibly spurious tumor cells carrying the secondary T790M mutation in the epidermal growth factor receptor (EGFRT790M mutants; yellow). Upon treatment with the targeted drug erlotinib, the majority of the tumor population is eradicated, but drug-tolerant persisters (red) survive and expand to generate drug-tolerant expanded persisters (DTEP, purple). DTP and DTEP are characterized by increased phosphorylation of the IGF-1 receptor (IGF-1R), increased expression of the histone demethylase KDM5A, reduced H3K4 methylation, and reduced H3K14 acetylation. Drug resistance of DTEP tumor cells is reversible as passaging these cells in the absence of erlotinib results in the emergence of a drug-sensitive heterogeneous tumor cell population. Treatment with chromatin-modifying drugs such as HDAC inhibitors eliminates DTPs and DTEPs but does not kill the vast majority of the PC9 parental tumor cell population. Concomitant treatment with erlotinib and HDAC inhibitors or IGF-1 receptor inhibitors results in effective ablation of drug-tolerant persisters thereby abrogating nongenetic drug resistance. Tumor cells surviving this treatment (yellow) have acquired genetic resistance due to secondary mutations (e.g., the T790M mutation) in EGFR.
Cell  , 18-20DOI: ( /j.cell )
Copyright © 2010 Elsevier Inc. Terms and Conditions