Stage-specific sensitivity to p53 restoration during lung cancer progression

Abstract

Tumourigenesis 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 toward pharmaceutical reactivation of defective p53 pathways are underway1–3. 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 signaling 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 signaling to mediate tumor 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.

KRAS mutant allele-specific imbalance in lung adenocarcinoma

“…7,10 Recently, it was shown that reactivation of p53 in a KRAS G12D mouse model of non-small-cell lung carcinoma lead to tumor regression only in tumors with KRAS signal elevated through the amplification of the mutant allele and loss of wild-type allele. 17,18 In this larger series of KRAS-mutated lung adenocarcinomas, we confirm and expand the finding that KRAS MASI correlates with worse clinical outcome. In this clinically homogenous cohort of KRAS-mutated lung adenocarcinomas, clinical stage was the only other prognostic factor that maintained its significance.…”

Screening for tumor suppressors: Loss of ephrin receptor A2 cooperates with oncogenic KRas in promoting lung adenocarcinoma

“…S5 E and F). It has been known that activation of ERK1/2 mitogen-activated protein kinase is a crucial downstream event following KRas-activating mutations in lung adenocarcinoma (18,31). So we first tested whether increased phosphorylation of ERK can be observed in vivo in EphA2 knockdown tumors compared with control tumors.…”

“…Negative feedback mechanisms inhibit downstream ERK1/2 and PI3K signaling cascades to cause senescence and to prevent transformation (52)(53)(54). Concomitant cooperative mutations in tumor suppressor proteins such as Tp53 help release this negative feedback in addition to affecting the genome stability (18,31). Further, cooperative loss of these feedback mechanisms was shown to promote Ras-induced leukemogenesis (50).…”

Molecular dynamics of the full-length p53 monomer

“…37 This results in significant changes in its functional properties as a transcription factor. [38][39][40][41][42][43] As a consequence of the p53 isoforms function as a transcription factor and its involvement in DNA damage, it is evident that the status of p53 plays a crucial role in cancer progression [44][45][46][47][48][49][50][51][52] as well in different physiological 2 and anticancer responses. 42 In fact, p53 is frequently mutated in cancer, resulting in novel "gain-of-function"effects.…”