RB status governs differential sensitivity to cytotoxic and molecularly-targeted therapeutic agents.
The retinoblastoma tumor suppressor (RB) is frequently inactivated in human cancers and has been shown to modulate the anti-proliferative effects of DNA-damaging therapies. However, the impact of RB loss on response to disparately functioning cytotoxic agents as well as targeted therapies is poorly understood. Here 3T3-immortalized and Ras-transformed mouse adult fibroblasts (MAFs) containing conditional RB alleles were utilized to investigate the consequence of RB loss on cellular response to cytotoxic agents and therapies targeting the MEK and PI3K pathways. Using these models, we demonstrate that RB deficiency is associated with bypass of therapy-induced checkpoints in response to both cytotoxic and targeted treatments. Interestingly, while checkpoint bypass following treatment with cytotoxic therapy results in an agent specific increase in drug sensitivity, checkpoint bypass following treatment targeting MEK and PI3K function results in increased cellular proliferation. These results indicate that RB status differentially impacts therapeutic response and should be considered when evaluating the efficacy of molecularly targeted therapeutics.
Stengel
Kristy R
KR
Experimental Hematology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
Dean
Jeffry L
JL
Seeley
Sarah L
SL
Mayhew
Christopher N
CN
Knudsen
Erik S
ES
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001973:Bromodeoxyuridine; D002070:Butadienes; D002461:Cell Line, Transformed; D002867:Chromones; D017931:DNA Primers / Q000235:genetics; D004591:Electrophoresis, Polyacrylamide Gel; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005347:Fibroblasts; D005434:Flow Cytometry; D015151:Immunoblotting; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism*; D051379:Mice; D009025:Morpholines; D009570:Nitriles; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D016133:Polymerase Chain Reaction; D016160:Retinoblastoma Protein / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*
D000970:Antineoplastic Agents; D002070:Butadienes; D002867:Chromones; D017931:DNA Primers; D004791:Enzyme Inhibitors; D009025:Morpholines; D009570:Nitriles; D016160:Retinoblastoma Protein; C113580:U 0126; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D019869:Phosphatidylinositol 3-Kinases; D020930:MAP Kinase Kinase Kinases; D001973:Bromodeoxyuridine