PTEN mutant non-small cell lung cancer require ATM to suppress pro-apoptotic signalling and evade radiotherapy

Fischer, Thomas; Hartmann, Oliver; Reissland, Michaela; Prieto-Garcia, Cristian; Klann, Kevin; Pahor, Nikolett; Schülein-Völk, Christina; Baluapuri, Apoorva; Polat, Bülent; Abazari, Arya; Gerhard-Hartmann, Elena; Kopp, Hans‐Georg; Eßmann, Frank; Rosenfeldt, Mathias T.; Münch, Christian; Flentje, Michael; Diefenbacher, Markus E.

doi:10.1186/s13578-022-00778-7

Cited by 10 publications

(4 citation statements)

References 79 publications

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“…Importantly, recent studies show that PTEN directly regulates resistance to radiation, chemo-, and immunotherapy [ 180 ]. The link between EMT and resistance to anticancer therapy has been reported in several reviews [ 10 , 181 , 182 ].…”

Section: Discussionmentioning

confidence: 99%

The Role of PTEN in Epithelial–Mesenchymal Transition

Fedorova

Parfenyev

Daks

et al. 2022

Cancers

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Phosphatase and Tensin Homolog deleted on Chromosome 10 (PTEN) is one of the critical tumor suppressor genes and the main negative regulator of the PI3K pathway. PTEN is frequently found to be inactivated, either partially or fully, in various malignancies. The PI3K/AKT pathway is considered to be one of the main signaling cues that drives the proliferation of cells. Perhaps it is not surprising, then, that this pathway is hyperactivated in highly proliferative tumors. Importantly, the PI3K/AKT pathway also coordinates the epithelial–mesenchymal transition (EMT), which is pivotal for the initiation of metastases and hence is regarded as an attractive target for the treatment of metastatic cancer. It was shown that PTEN suppresses EMT, although the exact mechanism of this effect is still not fully understood. This review is an attempt to systematize the published information on the role of PTEN in the development of malignant tumors, with a main focus on the regulation of the PI3K/AKT pathway in EMT.

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Section: Discussionmentioning

confidence: 99%

The Role of PTEN in Epithelial–Mesenchymal Transition

Fedorova

Parfenyev

Daks

et al. 2022

Cancers

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“…Furthermore, Fischer et al showed that PTEN mutant non-small-cell lung cancer requires ATM to suppress proapoptotic signaling and evade radiotherapy. Pharmacologic inhibition of ATM via KU-60019 and AZD1390 restores and even synergizes with ionizing radiation in PTEN-deficient human and murine NSCLC cells as well in ex vivo organotypic lung tumor slice cultures [ 53 ].…”

Section: Discussionmentioning

confidence: 99%

Cell-Free DNA Sequencing Reveals Gene Variants in DNA Damage Repair Genes Associated with Prognosis of Prostate Cancer Patients

Lieb

Abdulrahman

Weigelt

et al. 2022

Cells

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In the present study, we further analyzed the data obtained in our previous study, where we investigated the cell-free DNA (cfDNA) of 34 progressive prostate cancer patients via targeted sequencing. Here, we studied the occurrence and prognostic impact of sequence variants according to their clinical pathological significance (CPS) or their functional impact (FI) in 23 DNA damage repair (DDR) genes with a focus on the ATM serine/threonine kinase gene (ATM). All patients had at least one DDR gene with a CPS or FI variant. Kaplan‒Meier analysis indicated that the group with a higher number of CPS variants in DDR genes had a shorter time to treatment change (TTC) compared to the group with a lower number of CPS variants (p = 0.038). Analysis of each DDR gene revealed that CPS variants in the ATM gene and FI variants in the nibrin (NBN) gene showed a shorter TTC (p = 0.034 and p = 0.042). In addition, patients with CPS variants in the ATM gene had shorter overall survival (OS; p = 0.022) and disease-specific survival (DSS; p = 0.010) than patients without these variants. Interestingly, patients with CPS variants in seven DDR genes possessed a better OS (p = 0.008) and DSS (p = 0.009), and patients with FI variants in four DDR genes showed a better OS (p = 0.007) and DSS (p = 0.008). Together, these findings demonstrated that the analysis of cfDNA for gene variants in DDR genes provides prognostic information that may be helpful for future temporal and targeted treatment decisions for advanced PCa patients.

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“…In addition, miR-4461 was in part responsible for the resistance of OV cells to cisplatin [156]. Fischer et al [157] reported that PTEN-deficient tumors are addicted to the DNA damage kinase ataxia telangiectasia mutated kinase (ATM) in order to detect and repair induced DNA damage [157]. The use of low concentration of ATM inhibitor synergized with radiation to treat PTEN-deficient tumors in radiation-resistant lung cancer models [157].…”

Section: Resistance To Chemotherapymentioning

confidence: 99%

Cancer resistance via the downregulation of the tumor suppressors RKIP and PTEN expressions: therapeutic implications

Moghaddam

Vivarelli

Falzone

et al. 2023

Exploration of Targeted Anti-Tumor Therapy

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The Raf kinase inhibitor protein (RKIP) has been reported to be underexpressed in many cancers and plays a role in the regulation of tumor cells’ survival, proliferation, invasion, and metastasis, hence, a tumor suppressor. RKIP also regulates tumor cell resistance to cytotoxic drugs/cells. Likewise, the tumor suppressor, phosphatase and tensin homolog (PTEN), which inhibits the phosphatidylinositol 3 kinase (PI3K)/AKT pathway, is either mutated, underexpressed, or deleted in many cancers and shares with RKIP its anti-tumor properties and its regulation in resistance. The transcriptional and posttranscriptional regulations of RKIP and PTEN expressions and their roles in resistance were reviewed. The underlying mechanism of the interrelationship between the signaling expressions of RKIP and PTEN in cancer is not clear. Several pathways are regulated by RKIP and PTEN and the transcriptional and post-transcriptional regulations of RKIP and PTEN is significantly altered in cancers. In addition, RKIP and PTEN play a key role in the regulation of tumor cells response to chemotherapy and immunotherapy. In addition, molecular and bioinformatic data revealed crosstalk signaling networks that regulate the expressions of both RKIP and PTEN. These crosstalks involved the mitogen-activated protein kinase (MAPK)/PI3K pathways and the dysregulated nuclear factor-kappaB (NF-κB)/Snail/Yin Yang 1 (YY1)/RKIP/PTEN loop in many cancers. Furthermore, further bioinformatic analyses were performed to investigate the correlations (positive or negative) and the prognostic significance of the expressions of RKIP or PTEN in 31 different human cancers. These analyses were not uniform and only revealed that there was a positive correlation between the expression of RKIP and PTEN only in few cancers. These findings demonstrated the existence of signaling cross-talks between RKIP and PTEN and both regulate resistance. Targeting either RKIP or PTEN (alone or in combination with other therapies) may be sufficient to therapeutically inhibit tumor growth and reverse the tumor resistance to cytotoxic therapies.

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PTEN mutant non-small cell lung cancer require ATM to suppress pro-apoptotic signalling and evade radiotherapy

Cited by 10 publications

References 79 publications

The Role of PTEN in Epithelial–Mesenchymal Transition

The Role of PTEN in Epithelial–Mesenchymal Transition

Cell-Free DNA Sequencing Reveals Gene Variants in DNA Damage Repair Genes Associated with Prognosis of Prostate Cancer Patients

Cancer resistance via the downregulation of the tumor suppressors RKIP and PTEN expressions: therapeutic implications

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