Tissue-Specific Therapeutic Targeting of p53 in Cancer: One Size Does Not Fit All

Abstract

p53, the "guardian of the genome" and the most mutated gene in cancer presents a considerable therapeutic opportunity as well as a challenge. In the past decade, several therapeutic strategies have been developed that aim to take advantage of a wealth of knowledge about p53, including insights into the biology and patho-biology of p53. Nevertheless, considerable challenges remain, not least as a result of tissue- and cancer-specific differences in p53 regulation and/or function. p53 does not act in the same manner in all tissues or in the cancers arising from them. Nor is p53 regulated in the same way in the wide variety of tissues from which cancers develop. Therefore, potential strategies for therapeutic targeting need to be tailored to each tumour/tissue type. This review summarises some of these tissue- and cancer-specific issues to suggest how different strategies are required for cancers arising from different tissues and to illustrate the complexities of therapeutic targeting of p53.

Targeting p53 pathways: mechanisms, structures and advances in therapy

“…Hence a one-drug-fits-all approach may not be feasible for targeting TP53 mutations. 12 , 576 , 577 Therefore, different p53-targeting drugs may be required for different p53 mutants. Second, p53-targeted therapy alone may not be sufficient to treat cancer.…”

In vivo RNA-seq and ChIP-seq analyses show an obligatory role for the C terminus of p53 in conferring tissue-specific radiation sensitivity

“… 17 , 18 Multiple in vivo studies have revealed tissue specificity in p53-dependent gene expression. 20 – 25 Consistent with these DNA damage-triggered outcomes, restoration of p53 to tumors that arise because of p53 deletion show a distinct fate depending upon tissue, with sarcomas and liver carcinomas regressing because of senescence, while lymphomas undergo apoptosis. 26 , 27 It is noted that there is growing evidence that the p53 programs in response to acute DNA damage may be distinct from those involved in tumor suppression.…”

Hierarchical Nuclear Norm Penalization for Multi-View Data Integration

“…The p53 gene plays an important role in cell regulation with impact on aging processes and cancer (Seim et al., 2016; Tanikawa et al., 2017). However, the tissue‐specific nature of p53 gene expressions makes it difficult to develop targeted therapies (Vlatkovic et al., 2011). Thus, it is crucial to identify patterns in p53 gene expression that are shared and unique across multiple tissues.…”

“…The gene expression is often tissue‐specific. For instance, the p53 gene is critical for cell regulation playing prominent role in the cancer development (Tanikawa et al., 2017), however p53 tissue‐specific expression makes it difficult to develop targeted therapies (Vlatkovic et al., 2011). It is thus crucial to identify patterns in gene expression that are shared and unique across multiple tissues.…”