Mutant p53 in cancer: from molecular mechanism to therapeutic modulation

Chen, Xiaohua; Zhang, Taotao; Su, Wei; Dou, Zhihui; Zhao, Dapeng; Jin, Xiaodong; Lei, Huiwen; Wang, Jing; Xie, Xiaodong; Cheng, Bo; Li, Qiang; Zhang, Hong; Chen, Di

doi:10.1038/s41419-022-05408-1

Cited by 97 publications

(83 citation statements)

References 169 publications

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“…Truncating mutations in TP53 can potentially promote tumor growth. For example, the TP53 exon 6 truncating mutant R196* has been shown to facilitate tumor cell growth and metastasis ( Chen et al, 2022 ). TP53 gene mutations are found in approximately 50% of cases of NSCLC ( Mogi & Kuwano, 2011 ).…”

Section: Discussionmentioning

confidence: 99%

Meta-analysis of commonly mutated genes in leptomeningeal carcinomatosis

Congur

Koni

Onat

et al. 2023

PeerJ

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Background Leptomeningeal carcinomatosis (LMC) is a rare type of cancer that settles at the meninges through metastasis of non-small cell lung cancer (NSCLC), breast cancer and melanoma. The molecular mechanism underlying LMC is not known, therefore molecular studies investigating the development of LMC are needed. Here, we aimed to identify commonly mutated genes in LMC caused by NSCLC, breast cancer, and melanoma using an in-slico approach and their interactions using integrated bioinformatic approaches/tools in this meta-analysis. Methods We conducted a meta-analysis using information from 16 studies that included different sequencing techniques of patients with LMC caused by three different primary cancers: breast cancer, NSCLC, and melanoma. All studies that assessed mutation information from patients with LMC were searched in PubMed, from their inception to February, 16 2022. Studies that performed NGS on LMC patients with NSCLC, breast cancer, or melanoma were included, while studies that did not apply NGS to CSF samples, did not provide information on altered genes, were reviews, editorials, or conference abstracts, or whose main goal was the detection of malignancies were all excluded. We identified commonly mutated genes in all three types of cancer. Next, we constructed a protein-protein interaction network, then performed pathway enrichment analysis. We searched National Institutes of Health (NIH) and Drug-Gene Interaction Database (DGIdb) to find candidate drugs. Results We found that TP53, PTEN, PIK3CA, IL7R, and KMT2D genes were commonly mutated genes in all three types of cancer via our meta-analysis that consisted out of 16 studies. Our pathway enrichment analysis showed that all five genes were primarily associated with regulation of cell communication and signaling, and cell proliferation. Other enriched pathways included regulation of apoptotic processes of leukocytes and fibroblasts, macroautophagy and growth. According to our drug search we found candidate drugs; Everolimus, Bevacizumab and Temozolomide, which interact with these five genes. Conclusion In conclusion, a total of 96 mutated genes in LMC were investigated via meta-analysis. Our findings suggested vital roles of TP53, PTEN, PIK3CA, KMT2D, and IL7R, which can provide insight into the molecular basis of LMC development and paving the door to the development of new targeted medicine and will encourage molecular biologists to seek biological evidence.

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Section: Discussionmentioning

confidence: 99%

Meta-analysis of commonly mutated genes in leptomeningeal carcinomatosis

Congur

Koni

Onat

et al. 2023

PeerJ

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“…Many small molecule compounds with varying complexities have been designed to target both wild-type and mutant p53-bearing tumors, although most are still in pre-clinical stages of development [186]. Only a handful of candidate drugs have been investigated in early phase clinical trials involving breast cancer cases (Table 3) and the results have been mixed with modest efficacy signals and high-grade toxicities, in contrast to their promising pre-clinical results.…”

Section: Challenges In Developing Therapeutic Strategies Against P53 ...mentioning

confidence: 99%

Role of p53 in breast cancer progression: An insight into p53 targeted therapy

Marvalim¹,

Datta²,

Lee³

2023

Theranostics

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The transcription factor p53 is an important regulator of a multitude of cellular processes. In the presence of genotoxic stress, p53 is activated to facilitate DNA repair, cell cycle arrest, and apoptosis. In breast cancer, the tumor suppressive activities of p53 are frequently inactivated by either the overexpression of its negative regulator MDM2, or mutation which is present in 30-35% of all breast cancer cases. Notably, the frequency of p53 mutation is highly subtype dependent in breast cancers, with majority of hormone receptor-positive or luminal subtypes retaining the wild-type p53 status while hormone receptor-negative patients predominantly carry p53 mutations with gain-of-function oncogenic activities that contribute to poorer prognosis. Thus, a two-pronged strategy of targeting wild-type and mutant p53 in different subtypes of breast cancer can have clinical relevance. The development of p53-based therapies has rapidly progressed in recent years, and include unique small molecule chemical inhibitors, stapled peptides, PROTACs, as well as several genetic-based approaches using vectors and engineered antibodies. In this review, we highlight the therapeutic strategies that are in pre-clinical and clinical development to overcome p53 inactivation in both wild-type and mutant p53-bearing breast tumors, and discuss their efficacies and limitations in pre-clinical and clinical settings.

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“…These include small molecules and compounds subverting the oncogenic activities of mutant p53 into wild-type p53 tumor suppressor functions [326,327]. Gene therapy, for example, with the CRISPR/Cas9 system, immunotherapy (PC1CTM, INGN-225, or H2-scDb), or increased mutant p53 degradation are all possible future therapeutic directions [328]. In addition, further possible targeted treatments of TP53-driven tumors include mutant p53 synthetic lethal genes [328,329].…”

Section: Tp53mentioning

confidence: 99%

“…Gene therapy, for example, with the CRISPR/Cas9 system, immunotherapy (PC1CTM, INGN-225, or H2-scDb), or increased mutant p53 degradation are all possible future therapeutic directions [328]. In addition, further possible targeted treatments of TP53-driven tumors include mutant p53 synthetic lethal genes [328,329]. Additional therapeutic targets, such as mitochondria-targeted therapy, are also important in these tumors, which are often chemotherapy-resistant.…”

Section: Tp53mentioning

confidence: 99%

The Role of Genetic Mutations in Mitochondrial-Driven Cancer Growth in Selected Tumors: Breast and Gynecological Malignancies

Czegle

Huang

Soria

et al. 2023

Life

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There is an increasing understanding of the molecular and cytogenetic background of various tumors that helps us better conceptualize the pathogenesis of specific diseases. Additionally, in many cases, these molecular and cytogenetic alterations have diagnostic, prognostic, and/or therapeutic applications that are heavily used in clinical practice. Given that there is always room for improvement in cancer treatments and in cancer patient management, it is important to discover new therapeutic targets for affected individuals. In this review, we discuss mitochondrial changes in breast and gynecological (endometrial and ovarian) cancers. In addition, we review how the frequently altered genes in these diseases (BRCA1/2, HER2, PTEN, PIK3CA, CTNNB1, RAS, CTNNB1, FGFR, TP53, ARID1A, and TERT) affect the mitochondria, highlighting the possible associated individual therapeutic targets. With this approach, drugs targeting mitochondrial glucose or fatty acid metabolism, reactive oxygen species production, mitochondrial biogenesis, mtDNA transcription, mitophagy, or cell death pathways could provide further tailored treatment.

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Mutant p53 in cancer: from molecular mechanism to therapeutic modulation

Cited by 97 publications

References 169 publications

Meta-analysis of commonly mutated genes in leptomeningeal carcinomatosis

Meta-analysis of commonly mutated genes in leptomeningeal carcinomatosis

Role of p53 in breast cancer progression: An insight into p53 targeted therapy

The Role of Genetic Mutations in Mitochondrial-Driven Cancer Growth in Selected Tumors: Breast and Gynecological Malignancies

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