Stage-specific sensitivity to p53 restoration during lung cancer progression.
Tumorigenesis is a multistep process that results from the sequential accumulation of mutations in key oncogene and tumour suppressor pathways. Personalized cancer therapy that is based on targeting these underlying genetic abnormalities presupposes that sustained inactivation of tumour suppressors and activation of oncogenes is essential in advanced cancers. Mutations in the p53 tumour-suppressor pathway are common in human cancer and significant efforts towards pharmaceutical reactivation of defective p53 pathways are underway. Here we show that restoration of p53 in established murine lung tumours leads to significant but incomplete tumour cell loss specifically in malignant adenocarcinomas, but not in adenomas. We define amplification of MAPK signalling as a critical determinant of malignant progression and also a stimulator of Arf tumour-suppressor expression. The response to p53 restoration in this context is critically dependent on the expression of Arf. We propose that p53 not only limits malignant progression by suppressing the acquisition of alterations that lead to tumour progression, but also, in the context of p53 restoration, responds to increased oncogenic signalling to mediate tumour regression. Our observations also underscore that the p53 pathway is not engaged by low levels of oncogene activity that are sufficient for early stages of lung tumour development. These data suggest that restoration of pathways important in tumour progression, as opposed to initiation, may lead to incomplete tumour regression due to the stage-heterogeneity of tumour cell populations.
Koch Institute for Integrative Cancer Research, Department of Biology, and Howard Hughes Medical Institute, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA.
David M
DM
Feldser
Kamena K
KK
Kostova
Monte M
MM
Winslow
Sarah E
SE
Taylor
Chris
C
Cashman
Charles A
CA
Whittaker
Francisco J
FJ
Sanchez-Rivera
Rebecca
R
Resnick
Roderick
R
Bronson
Michael T
MT
Hemann
Tyler
T
Jacks
D000230:Adenocarcinoma / Q000378:metabolism / Q000503:physiopathology*; D000236:Adenoma / Q000378:metabolism / Q000503:physiopathology*; D000818:Animals; D049109:Cell Proliferation; D018450:Disease Progression; D008175:Lung Neoplasms / Q000503:physiopathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D015398:Signal Transduction; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
D016159:Tumor Suppressor Protein p53; D020928:Mitogen-Activated Protein Kinases