Chk2 deficiency in Myc overexpressing lymphoma cells elicits a synergistic lethal response in combination with PARP inhibition.
Myc is a transcription factor frequently found deregulated in human cancer. The Myc-mediated cellular transformation process is associated with fast proliferative cells and inherent genomic instability, giving rise to malignant, invasive neoplasms with poor prognosis for survival. Transcription-independent functions of Myc include stimulation of replication. Excessive Myc expression stimulates a replication-associated DNA damage response that signals via the phosphoinositide-3-kinase (PI3K)-related protein kinases (PIKKs) ATM and ATR. These, in turn, activate the DNA damage transducers Chk1 and Chk2. Here, we show that Myc can stimulate Chek2 transcript indirectly in vitro as well as in B cells of λ-Myc transgenic mice or in the intestine of Apc (Min)  mice. However, Chk2 is dispensable for Myc's ability to transform cells in vitro and for the survival of established lymphoma cells from λ-Myc transgenic mice. Chk2 deficiency induces polyploidy and slow growth, but the cells are viable and protected against DNA damage. Furthermore, inhibition of both Chk1/Chk2 with AZD7762 induces cell death and significantly delays disease progression of transplanted lymphoma cells in vivo. DNA damage recruits PARP family members to sites of DNA breaks that, in turn, facilitate the induction of DNA repair. Strikingly, combining Chk2 and PARP inhibition elicits a synergistic lethal response in the context of Myc overexpression. Our data indicates that only certain types of chemotherapy would give rise to a synergistic lethal response in combination with specific Chk2 inhibitors, which will be important if Chk2 inhibitors enter the clinic.
Department of Molecular Biology, Umeå University, Umeå, Sweden.
Andreas
A
Höglund
Kerstin
K
Strömvall
Yongmei
Y
Li
Linus Plym
LP
Forshell
Jonas A
JA
Nilsson
D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D002460:Cell Line; D064447:Checkpoint Kinase 2; D004249:DNA Damage / Q000235:genetics*; D005455:Fluorescent Antibody Technique; D006801:Humans; D016086:Lentivirus; D008223:Lymphoma / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D041681:NIH 3T3 Cells; D000071137:Poly (ADP-Ribose) Polymerase-1; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000172:deficiency*; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism*; D012190:Retroviridae; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016019:Survival Analysis; D013876:Thiophenes / Q000494:pharmacology; D014162:Transfection; D014508:Urea / Q000031:analogs & derivatives / Q000494:pharmacology
C532363:3-(carbamoylamino)-5-(3-fluorophenyl)-N-(3-piperidyl)thiophene-2-carboxamide; C489428:Myc protein, mouse; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D016271:Proto-Oncogene Proteins c-myc; D013876:Thiophenes; D014508:Urea; C499321:Parp1 protein, mouse; D000071137:Poly (ADP-Ribose) Polymerase-1; D064447:Checkpoint Kinase 2; C578634:CHEK2 protein, human; C578633:Chek2 protein, mouse; D017346:Protein Serine-Threonine Kinases