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Role of p53 Family in Targeted Therapy of Cancers
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Role of p53 Family in Targeted Therapy of Cancers

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Oncology".

Deadline for manuscript submissions: 20 July 2024 | Viewed by 2108

Special Issue Editors

Dr. Ignacija Vlasic

E-Mail Website
Guest Editor
Laboratory for Protein Dynamics, Division of Molecular Medicine, Ruđer Bošković Institute, Bijenička 54, 10000 Zagreb, Croatia
Interests: cancer; transcription factors; p53 family members; p53 isoforms; isoform crosstalk; targeted therapy; resistance to therapy
Dr. Neda Slade

E-Mail Website
Guest Editor
Institut Ruđer Bošković, Bijenička cesta 54, 10000 Zagreb, Croatia
Interests: p53 family of proteins; p53 isoforms; metastatic melanoma; protein interactions; BRAF inhibitors; resistance
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The p53 family comprises three transcription factors, p53, p63 and p73, that exhibit diverse biological activities. To understand the functioning of the p53 pathway, all family members should be considered. Their main function in normal cells is the maintenance of genome stability and cell homeostasis. However, their tumour suppressor function is abrogated in the majority of cancer cells due to mutations or altered expression of specific isoforms. p53 family isoforms form homotetramers or heterotetramers and this can change the function of canonical p53 proteins, thus influencing the p53 signalling pathway, causing cancer progression or even resistance to therapy. Accordingly, many p53 family members/isoforms are shown to be the modulators of acquired resistance to targeted cancer therapy. However, the prognostic relevance in the clinics is attributed only to mutant p53. Different strategies have been investigated for targeting p53-dysfunctional cancers using small molecules and several compounds have already reached clinical trials. Therefore, p53 family members/isoforms are potential targets for cancer therapy whose activity can potentially be modulated with the aim to re-establish a functional p53 pathway.

This Special Issue focuses on the role of the p53 family members in cancer therapy, their function as modulators of the therapy response and their potential as predictive or prognostic markers as well as therapeutic targets.

This special issue is supervised by Dr. Ignacija Vlasic and Dr. Neda Slade, and assisted by our Topical Advisory Panel Member Dr. Anđela Horvat (Ruđer Bošković Institute, Croatia).

Dr. Ignacija Vlasic
Dr. Neda Slade
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • p53 family of proteins
  • p53 family isoforms/splice variants
  • p53 family crosstalk
  • mutant p53
  • altered expression of p53 family members/isoforms
  • cancer progression
  • targeted therapy
  • therapy resistance

Published Papers (1 paper)

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Research

14 pages, 1450 KiB  
Article
Targeting Oncogenic Mutant p53 and BCL-2 for Small Cell Lung Cancer Treatment
by Victoria Neely, Alekhya Manchikalapudi, Khanh Nguyen, Krista Dalton, Bin Hu, Jennifer E. Koblinski, Anthony C. Faber, Sumitra Deb and Hisashi Harada
Int. J. Mol. Sci. 2023, 24(17), 13082; https://doi.org/10.3390/ijms241713082 - 23 Aug 2023
Viewed by 1638
Abstract
Through a unique genomics and drug screening platform with ~800 solid tumor cell lines, we have found a subset of SCLC cell lines are hypersensitive to venetoclax, an FDA-approved inhibitor of BCL-2. SCLC-A (ASCL1 positive) and SCLC-P (POU2F3 positive), which make up almost [...] Read more.
Through a unique genomics and drug screening platform with ~800 solid tumor cell lines, we have found a subset of SCLC cell lines are hypersensitive to venetoclax, an FDA-approved inhibitor of BCL-2. SCLC-A (ASCL1 positive) and SCLC-P (POU2F3 positive), which make up almost 80% of SCLC, frequently express high levels of BCL-2. We found that a subset of SCLC-A and SCLC-P showed high BCL-2 expression but were venetoclax-resistant. In addition, most of these SCLC cell lines have TP53 missense mutations, which make a single amino acid change. These mutants not only lose wild-type (WT) p53 tumor suppressor functions, but also acquire novel cancer-promoting activities (oncogenic, gain-of-function). A recent study with oncogenic mutant (Onc)-p53 knock-in mouse models of SCLC suggests gain-of-function activity can attenuate chemotherapeutic efficacy. Based on these observations, we hypothesize that Onc-p53 confers venetoclax resistance and that simultaneous inhibition of BCL-2 and Onc-p53 induces synergistic anticancer activity in a subset of SCLC-A and SCLC-P. We show here that (1) down-regulation of Onc-p53 increases the expression of a BH3-only pro-apoptotic BIM and sensitizes to venetoclax in SCLC-P cells; (2) targeting Onc-p53 by the HSP90 inhibitor, ganetespib, increases BIM expression and sensitizes to venetoclax in SCLC-P and SCLC-A cells. Although there are currently many combination studies for venetoclax proposed, the concept of simultaneous targeting of BCL-2 and Onc-p53 by the combination of venetoclax and HSP90 inhibitors would be a promising approach for SCLC treatment. Full article
(This article belongs to the Special Issue Role of p53 Family in Targeted Therapy of Cancers)
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