PTEN in Colorectal Cancer: Shedding Light on Its Role as Predictor and Target
Abstract
:1. Introduction
2. PTEN in CRC
3. PTEN as a Predictive Factor
4. PTEN as a Target
5. Future Perspectives
6. Conclusions
Author Contributions
Funding
Conflicts of Interest
References
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Study | No. of Patients | Treatment | PTEN Assessment | RR | PFS | OS | |
---|---|---|---|---|---|---|---|
Frattini et al. 2007 [24] | Prospective | 27 | Cet-based | IHC | PTEN+ vs. PTEN− 62.5% vs. 0% (p > 0.001) | - | - |
Loupakis et al. 2009 [25] | Retrospective | 59 | Iri + Cet | IHC | PTEN+ vs. PTEN− Higher RR (p = 0.007) | PTEN+ vs. PTEN- 4.7 vs. 3.3 m (HR = 0.49; p = 0.005) | - |
Laurent-Puig et al. 2009 [26] | Retrospective | 162 | Cet-based | IHC | - | - | PTEN- associated with shorter OS (p = 0.013) |
Therkildsen et al. 2014 [55] | Meta-analysis | 100 (9 studies) | Anti-EGFR based | Protein expression (7 studies) Mutational status (2 studies) | PTEN- Odds Ratio = 0.41 (95%CI = 0.20–0.85) | PTEN- associated with shorter PFS (HR 1.88, 95%CI = 1.35–2.61) | PTEN- associated with shorter OS (HR = 2.09, 95%CI = 1.36–3.19) |
Karapetis et al. 2014 [28] | CO.17 trial Prespecified subgroup analysis | 205 | Cet | IHC | PTEN+ vs. PTEN− 21% vs. 15% | - | No association between PTEN status and OS Among PTEN+ OS 9.9 vs. 5.4 months for Cet vs. BSC (HR = 0.66; p = 0.32) |
Agoston et al. 2016 [27] | Retrospective | 55 | Anti-EGFR based | IHC | - | - | No association between PTEN status and OS |
Kara et al. 2012 [35] | Retrospective | 34 | Bev based | IHC | PTEN+ vs. PTEN− p = 0.832 | - | PTEN+ vs. PTEN− p = 0.6 |
Price et al. 2013 [12] | AGITG MAX trial, post hoc analysis | 302 | Bev based | CNV | PTEN+ vs. PTEN− p = 0.36 | PTEN+ vs. PTEN− p = 0.26 | PTEN+ vs. PTEN− p = 0.35 |
Sclafani et al. 2015 [36] | Retrospective | 42 | Bev based | IHC | PTEN− vs. PTEN+ 71.4% vs. 32.1% p = 0.02 | PTEN− vs. PTEN+ 9.2 vs. 8.7 months p = 0.968 | PTEN− vs. PTEN+ 21.1 vs. 17.3 months p = 0.628 |
Weldone Gilcrease et al. 2019 [46] | Post hoc analysis (phase I/II) | 24 | Eve+mFOLFOX6-Bev | IHC | PTEN+ vs. PTEN− 40% vs. 86% p = 0.03 | - | - |
Moroney J et al. 2012 [48] | Prospective (phase I) | 136 (including 17 with mCRC) | Tem+Bev+liposomial doxo | PCR and IHC | PIK3CA MT and/or PTEN loss/MT vs. WT 39% vs. 16%, p = 0.018 | ||
Corcoran RB et al. 2015 [49] | Prospective (phase I/II) | 19 | Dabrafenib+ Trametinib | IHC | PTEN− vs. PTEN+ 21% vs. 0% | PTEN− vs. PTEN+ 3.48 vs. 3.61 months p = 0.35 | - |
Pishvaian et al. 2018 [50] | Prospective (phase II) | 49 | Veli+Temo | IHC | PTEN− vs. PTEN+ 13.3% vs. 21.1% | PTEN− vs. PTEN+ 1.7 vs. 1.8 months | PTEN- vs. PTEN+ 6.2 vs. 6.3 months |
Level | Strategy | Agents | Evidences | Reference |
---|---|---|---|---|
Transcriptional level | Removing epigenetic inhibition | DNA methyltransferase inhibitors | Decitabine proved to be safe and active in combination with panitumumab in KRAS wt mCRC patients previously treated with cetuximab. Decitabine proved to be safe when administered by hepatic arterial infusion in liver limited mCRC patients. | [58] [59] |
Increasing exposure to activating transcription factors | Rosiglitazone Irradiation Butyrate | Some transcription factors can be pharmacologically stimulated: PPARγ (via rosiglitazone), EGR-1 (via irradiation), NFAT (via butyrate). | [56] | |
Reducing exposure to inhibiting transcription factors | Statins NF-κB selective inhibitors | The inhibiting transcription factor NF-κB can be repressed through statins or selective inhibitors. | [56] | |
Post-transcriptional level | Inhibiting miRNAs and RNA binding proteins | Anti-miRNA-221 | Anti-miRNA-221 showed to increase PTEN expression, sensitizing CRC cells to radiation. | [64] |
Butylcycloheptyl prodiginine | Butylcycloheptyl prodiginine showed to suppress miR-21 and consequently cellular growth in CRC lines. | [65] | ||
miR-543 inhibitor | A miR-543 inhibitor proved to reverse chemoresistance to 5-fluorouracil (5-FU), obtained by this oncomir through reduction of PTEN expression, enhancing cellular sensitivity to 5-FU. | [66] | ||
PD0325901 | PD0325901 (a MEK inhibitor) proved to upregulate PTEN by suppressing miR-17-92 cluster. | [67] | ||
PTENpg1 | PTENpg1, a long, non-coding RNA transcripted by the PTEN pseudogene (PTENpg1) was shown to saturate miRNAs. | [68] | ||
Gossypol | Gossypol showed to inhibit Musashi-1/2 proteins and demonstrated antitumoral activity in a xenograft model. | [63] | ||
Post-translational level | Targeting enzymes involved in post-translational modification or reverting post-translational modification | Casein kinase 2 inhibitor | Inhibitor of casein kinase 2 (a serine/threonine kinase, which phosphorylates PTEN, causing repression of its catalytic activity) showed to reduce cell growth and invasiveness in CRC lines. | [73] |
Linc02023 | Linc02023 (a long non coding RNA) was shown to impair PTEN ubiquitination and subsequent degradation, inhibiting CRC cell proliferation and in vitro and in vivo survival. | [74] | ||
Paracrine function | PTEN-L | PTEN-L, an PTEN isoform with a paracrine function, showed to counteract the PI3K/Akt pathway both in vitro and in vivo (through intraperitoneal infusion in xenograft models). | [71] | |
Target protein–protein interaction | Curcumin | Curcumin was shown to inhibit proliferation and promote apoptosis via the downregulation of DJ-1 (a PTEN negative modulator) in CRC cell lines. | [78] | |
Ribonuclease inhibitor | Upregulation of a ribonuclease inhibitor was shown to stimulate PTEN expression, leading to PI3K/Akt pathway suppression in CRC cell lines. | [79] |
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Share and Cite
Salvatore, L.; Calegari, M.A.; Loupakis, F.; Fassan, M.; Di Stefano, B.; Bensi, M.; Bria, E.; Tortora, G. PTEN in Colorectal Cancer: Shedding Light on Its Role as Predictor and Target. Cancers 2019, 11, 1765. https://doi.org/10.3390/cancers11111765
Salvatore L, Calegari MA, Loupakis F, Fassan M, Di Stefano B, Bensi M, Bria E, Tortora G. PTEN in Colorectal Cancer: Shedding Light on Its Role as Predictor and Target. Cancers. 2019; 11(11):1765. https://doi.org/10.3390/cancers11111765
Chicago/Turabian StyleSalvatore, Lisa, Maria Alessandra Calegari, Fotios Loupakis, Matteo Fassan, Brunella Di Stefano, Maria Bensi, Emilio Bria, and Giampaolo Tortora. 2019. "PTEN in Colorectal Cancer: Shedding Light on Its Role as Predictor and Target" Cancers 11, no. 11: 1765. https://doi.org/10.3390/cancers11111765