Monoclonal Antibodies against Specific p53 Hotspot Mutants as Potential Tools for Precision Medicine

Hwang, Le-Ann; Phang, Beng Hooi; Liew, Oi Wah; Iqbal, Jabed; Koh, Xiao Hui; Koh, Xin Yu; Othman, Rashidah; Xue, Yuezhen; Richards, A. Mark; Lane, David P.; Sabapathy, Kanaga

doi:10.1016/j.celrep.2017.11.112

Cited by 37 publications

(28 citation statements)

References 50 publications

(67 reference statements)

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“…Diagnostic-level next generation monoclonal antibodies against specific mutp53 hotspot mutations might be useful here. A first step was done by Hwang and coworkers who generated mutp53-specific antibodies against three of the most common p53 hotspot mutations [ 98 ].…”

Section: Discussionmentioning

confidence: 99%

Gain-of-Function (GOF) Mutant p53 as Actionable Therapeutic Target

Schulz-Heddergott

Moll

2018

Cancers

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p53 missense mutant alleles are present in nearly 40% of all human tumors. Such mutated alleles generate aberrant proteins that not only lose their tumor-suppressive functions but also frequently act as driver oncogenes, which promote malignant progression, invasion, metastasis, and chemoresistance, leading to reduced survival in patients and mice. Notably, these oncogenic gain-of-function (GOF) missense mutant p53 proteins (mutp53) are constitutively and tumor-specific stabilised. This stabilisation is one key pre-requisite for their GOF and is largely due to mutp53 protection from the E3 ubiquitin ligases Mdm2 and CHIP by the HSP90/HDAC6 chaperone machinery. Recent mouse models provide convincing evidence that tumors with highly stabilized GOF mutp53 proteins depend on them for growth, maintenance, and metastasis, thus creating exploitable tumor-specific vulnerabilities that markedly increase lifespan if intercepted. This identifies mutp53 as a promising cancer-specific drug target. This review discusses direct mutp53 protein-targeting drug strategies that are currently being developed at various preclinical levels.

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Section: Discussionmentioning

confidence: 99%

Gain-of-Function (GOF) Mutant p53 as Actionable Therapeutic Target

Schulz-Heddergott

Moll

2018

Cancers

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“…The specificity of these antibodies has been validated in a number of assays, including IHC of human tumour tissues. The potential use of these mutation‐specific antibodies in personalised medicine is currently being explored . Our recent review discussed several available antibodies used to study p53 .…”

Section: Combined P53 Protein/mrna Detection and The Use Of Mutant‐spmentioning

confidence: 99%

Intratumour heterogeneity of p53 expression; causes and consequences

Xue

Luis

Lane

2019

The Journal of Pathology

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Genomic alterations in different types of cancer have been identified by comprehensive sequencing methodologies, revealing TP53 as the most frequently mutated gene across the majority of human cancer types. Cytotoxic treatments are still major cancer therapy strategies but cancer recurrence due to therapy resistance is a major challenge. Resistant cell populations may be associated with TP53 mutant clones exhibiting abnormal p53 expression patterns in tumours. Given data that levels of mutant p53 influence cancer cell growth and survival, understanding the mechanisms underlying intratumour heterogeneity of p53 can be exploited to design strategies that improve patient survival. The patterns of p53 protein examined by immunohistochemistry of both premalignant and malignant tissues are complex, ranging from intense staining of all tumour cell nuclei to complete absence of staining and with many intermediate phenotypes. Animal models that express only mutant proteins and adoption of international standards for terminology have brought greater clarity to understanding the causes of variation and are at the same time demonstrating the utility of p53 in oncology. In addition to p53 mutation, MDM2 and chaperone activities, gene copy number and TP53 mRNA levels linked to proliferative activity and differentiation are all now established as causes of variation in p53 staining, with clinical implications. © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

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“…There are many different antibodies to detect mutant forms of proteins by immunohistochemistry in formalin-fixed paraffin-embedded (FFPE) cancer tissues. BRAF, KRAS, and p53 are examples of cancer-related proteins for which mutation-specific antibodies for immunohistochemistry are commercially available [11][12][13]. Here, we describe an immunohistochemical method that can be used to study Wnt pathway defects in primary neoplastic tissues.…”

Section: Introductionmentioning

confidence: 99%

An immunohistochemical approach to detect oncogenic CTNNB1 mutations in primary neoplastic tissues

Akyol

Güner

Özşeker

et al. 2019

Laboratory Investigation

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The Wnt/β-catenin signaling pathway is dysregulated in different types of neoplasms including colorectal cancer (CRC). Aberrant activation of this signaling pathway is a key early event in the development of colorectal neoplasms, and is mainly caused by loss of function mutations in Adenomatous Polyposis Coli (APC), and less frequently by β-catenin stabilization mutations via missense or interstitial genomic deletions in CTNNB1. In this study, we have defined an immunohistochemical algorithm to dissect Wnt pathway alterations in formalin-fixed and paraffin-embedded neoplastic tissues. Basically, consecutive sections of tumor specimens were stained by immunohistochemistry with two different monoclonal antibodies against β-catenin: one (anti-active β-catenin antibody) recognizes hypo-phosphorylated β-catenin and the other recognizes the total pool of β-catenin. We validated the strategy in the HCT116 CRC cell line which has an in-frame deletion of β-catenin serine 45, and then studied human tumor microarrays containing colon adenomas, CRCs, solid pseudopapillary neoplasms of the pancreas as well as the whole tissue sections of CRCs, desmoid fibromatosis, and pilomatrixoma of the skin. In some tumors, we found strong β-catenin cytoplasmic and/or nuclear staining with the total β-catenin antibody but no staining with the anti-active β-catenin antibody. This was inferred to be an altered/mutant β-catenin staining pattern. All six colon adenomas of the 126 total adenomas studied for the altered/mutant β-catenin staining pattern had presumptively pathogenic point mutations or deletions in CTNNB1. Four of 10 CRCs with the alterated/mutant β-catenin staining pattern studied in depth, from 181 total CRCs from tissue microarray, had pathogenic CTNNB1 mutations. The frequencies of CTNNB1 alterations in non-colonic tumors with altered/mutant β-catenin staining ranged between 46 and 100%. Our results demonstrate that the immunohistochemical approach described here can detect oncogenic forms of β-catenin in primary tissue samples and can also highlight other tumors with presumptive novel defects activating the Wnt/β-catenin pathway.

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Monoclonal Antibodies against Specific p53 Hotspot Mutants as Potential Tools for Precision Medicine

Cited by 37 publications

References 50 publications

Gain-of-Function (GOF) Mutant p53 as Actionable Therapeutic Target

Gain-of-Function (GOF) Mutant p53 as Actionable Therapeutic Target

Intratumour heterogeneity of p53 expression; causes and consequences

An immunohistochemical approach to detect oncogenic CTNNB1 mutations in primary neoplastic tissues

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