TY - JOUR
T1 - Context dependence of checkpoint kinase 1 as a therapeutic target for pancreatic cancers deficient in the BRCA2 tumor suppressor
AU - Hattori, Hiroyoshi
AU - Skoulidis, Ferdinandos
AU - Russell, Paul
AU - Venkitaraman, Ashok R.
PY - 2011/4
Y1 - 2011/4
N2 - Inherited mutations in the tumor suppressor BRCA2 are predisposed to pancreatic adenocarcinomas, which carry activating mutations in the KRAS oncogene in more than 95% of cases, as well as frequent TP53 inactivation. Here, we have established an RNA interference (RNAi) screen to identify genes whose depletion selectively inhibits the growth of cells lacking BRCA2, and then studied the effects of the genetic depletion or pharmacologic inhibition of 1 candidate, the checkpoint kinase 1 (CHK1), in the context of pancreatic cancer. Pharmacologic inhibition of CHK1 using small-molecule inhibitors (CHK1i) reduced cell growth in several cell lines depleted of BRCA2. Unexpectedly, these drugs did not suppress the growth of BRCA2-deficient pancreatic cancer cell lines from humans or gene-targeted mice expressing active Kras and trans-dominant inhibitory mutant Trp53. Remarkably, the expression of KRASG12V and TP53G154V in BRCA2-depleted HEK293 cells was sufficient to render them resistant to CHK1i (but not to mitomycin C or inhibitors of PARP1). CHK1i sensitivity was restored by gemcitabine, an S-phase genotoxin used to treat pancreatic adenocarcinoma. Thus, the growth-suppressive effect of CHK1 inhibition in BRCA2-mutant tumors can be opposed by concurrent KRAS activation and TP53 mutations typical of pancreatic adenocarcinoma, and CHK1i resistance in this setting can be overcome by gemcitabine. Our findings show that approaches that use potential therapeutic targets for cancer identified in synthetic lethal RNAi screens are affected by the genetic context of specific malignancies and combination therapy with other agents. This concept should be taken into account in the ongoing and future development of targeted cancer therapies.
AB - Inherited mutations in the tumor suppressor BRCA2 are predisposed to pancreatic adenocarcinomas, which carry activating mutations in the KRAS oncogene in more than 95% of cases, as well as frequent TP53 inactivation. Here, we have established an RNA interference (RNAi) screen to identify genes whose depletion selectively inhibits the growth of cells lacking BRCA2, and then studied the effects of the genetic depletion or pharmacologic inhibition of 1 candidate, the checkpoint kinase 1 (CHK1), in the context of pancreatic cancer. Pharmacologic inhibition of CHK1 using small-molecule inhibitors (CHK1i) reduced cell growth in several cell lines depleted of BRCA2. Unexpectedly, these drugs did not suppress the growth of BRCA2-deficient pancreatic cancer cell lines from humans or gene-targeted mice expressing active Kras and trans-dominant inhibitory mutant Trp53. Remarkably, the expression of KRASG12V and TP53G154V in BRCA2-depleted HEK293 cells was sufficient to render them resistant to CHK1i (but not to mitomycin C or inhibitors of PARP1). CHK1i sensitivity was restored by gemcitabine, an S-phase genotoxin used to treat pancreatic adenocarcinoma. Thus, the growth-suppressive effect of CHK1 inhibition in BRCA2-mutant tumors can be opposed by concurrent KRAS activation and TP53 mutations typical of pancreatic adenocarcinoma, and CHK1i resistance in this setting can be overcome by gemcitabine. Our findings show that approaches that use potential therapeutic targets for cancer identified in synthetic lethal RNAi screens are affected by the genetic context of specific malignancies and combination therapy with other agents. This concept should be taken into account in the ongoing and future development of targeted cancer therapies.
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U2 - 10.1158/1535-7163.MCT-10-0781
DO - 10.1158/1535-7163.MCT-10-0781
M3 - Article
C2 - 21289082
AN - SCOPUS:79955758170
SN - 1535-7163
VL - 10
SP - 670
EP - 678
JO - Molecular cancer therapeutics
JF - Molecular cancer therapeutics
IS - 4
ER -