The Consequence of Oncomorphic TP53 Mutations in Ovarian Cancer

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(This article belongs to the Special Issue Genes and Pathways in the Pathogenesis of Ovarian Cancer)

 

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Abstract:  

 

Ovarian cancer is the most lethal gynecological malignancy, with an alarmingly poor prognosis attributed to late detection and chemoresistance. Initially, most tumors respond to chemotherapy but eventually relapse due to the development of drug resistance. Currently, there are no biological markers that can be used to predict patient response to chemotherapy. However, it is clear that mutations in the tumor suppressor gene TP53, which occur in 96% of serous ovarian tumors, alter the core molecular pathways involved in drug response. One subtype of TP53 mutations, widely termed gain-of-function (GOF) mutations, surprisingly converts this protein from a tumor suppressor to an oncogene. We term the resulting change an oncomorphism. In this review, we discuss particular TP53 mutations, including known oncomorphic properties of the resulting mutant p53 proteins. For example, several different oncomorphic mutations have been reported, but each mutation acts in a distinct manner and has a different effect on tumor progression and chemoresistance. An understanding of the pathological pathways altered by each mutation is necessary in order to design appropriate drug interventions for patients suffering from this deadly disease.

 

"...One alternative approach is the idea of restoring WT p53 function. The concept of restoring WT
p53 activity is strongly supported by in vitro and in vivo studies as well as several clinical trials
showing that restoration of WT p53 function causes rapid tumor regression in mice and prolonged
survival in humans [101–105]. Various strategies have been employed with the ultimate goal of
restoring WT p53 function. The most common method used to date is gene therapy, namely
introducing a copy of the WT TP53 gene into tumors using an adenovirus. Excitingly, 50% (8 of 16)
women with recurrent ovarian, peritoneal, or fallopian tube cancer that were treated with the
replication-deficient adenovirus encoding human recombinant WT TP53 (SCH 58500) showed a
decrease in serum CA125 levels, indicative of clinical response, with minimal side effects [104].
Moreover, combination of WT TP53 gene therapy with chemotherapeutic drugs such as cisplatin
synergized to enhance clinical efficacy [104]. Unfortunately, an international randomized phase II/III
trial of WT TP53 gene therapy in ovarian cancer was closed after the first interim analysis because
adequate therapeutic benefit was not achieved [105]. A limitation of these studies may have been the presence of an oncomorphic p53 protein that could impose a dominant negative effect on the
therapeutic WT p53 and impede success.
Other approaches such as targeting cellular proteins responsible for stabilizing mutant p53 are
another route that may bring success. A recent development involves inhibiting the heat-shock protein HSP90, which chaperones many mutant p53 proteins [106,107] and prevents their degradation by the E3 ubiquitin ligase MDM2 [108,109]. The interaction between the heat shock protein and its client proteins can be disrupted by acetylation of HSP90, posing an exciting opportunity for the use of HSP90 inhibitors as well as deacetylase inhibitors such as the FDA-approved SAHA (Vorinostat) [110,111].

 

"In summary, the information gained from studying the mutant p53 transcriptome and interactome
described in this review has solidified the foundation for the development of strategies that can one
day be used to treat the large number of cancer patients that harbor TP53 mutations."