The p53 gene is the major tumor suppressor in humans and is generally found mutated in over 50% of all human cancers.
The dominant-negative (DN) effect of the mutant p53 gene in cancers was found to affect the outcome of cancer treatment modalities. DN effect is a phenomenon whereby one copy of mutant p53 that exists in cancer cells inhibits the tumor suppressor activity of the other wild-type p53 copy when they co-exist. The result is that a patient may either have poor response or earlier relapse of tumours after their treatment.
The research findings is significant in that it offers hope to improve cancer treatment outcomes by selectively inhibiting mutant p53's DN effect through several methods by generating selective and specific inhibitory molecules specific for some of the common hot-spot p53 point mutations. There are currently no drugs or compounds that can alleviate DN effects of mutant p53.
In order to understand the specific roles of mutant p53 DN properties in regulating acute treatment response and long-term tumourgenesis, a team of five researchers led by NCCS Prof Kanaga Sabapathy, the Principal Investigator in the Laboratory of Carcinogenesis and Head of the Division of Cellular & Molecular Research from NCCS, carried out experiments by generating genetically engineered knock-in mouse strains expressing varying levels of mutant p53. The results showed that DN effect is observed after acute p53 activation by a variety of chemotherapeutic drugs and irradiation, thereby affecting anti-cancer treatment.
It was found that mutant p53 have DN effects in a cell-type and dose-dependent manner, especially during acute p53 activation where p53 levels are elevated. Based on the above observations, efforts to generate specific inhibitors for the common hot spot p53 point mutations are underway. The inhibition of mutant p53 expression in cells carrying a wild-type and mutant p53 alleles can improve response to chemotherapeutic drugs.