Preclinical Evidence for Targeting PI3K/mTOR Signaling with Dual-Inhibitors as a Therapeutic Strategy against Cutaneous T-Cell Lymphoma

Bresin, Antonella; Cristofoletti, Cristina; Caprini, Elisabetta; Cantonetti, Maria; Monopoli, Alessandro; Russo, Giandomenico; Narducci, Maria Grazia

doi:10.1016/j.jid.2019.08.454

Cited by 23 publications

(28 citation statements)

References 59 publications

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“…Combination of BRAF and MEK inhibitors was more efficient than BRAF inhibitor alone in BRAF‐mutant melanoma and non–small cell lung cancer; it even showed a prolonged overall survival in a CRC clinical trial 41‐45 . Moreover, dual inhibitors of PI3K/MTOR displayed a stronger effect than MTOR inhibitor alone in not only hematological tumors but also solid tumors 46‐48 . Furthermore, based on our data, depleting the signaling intermediates together with KRAS or PIK3CA provided not only better antitumor effects but also stronger signaling inhibition than single‐depletion.…”

Section: Discussionmentioning

confidence: 62%

Quadruple‐editing of the MAPK and PI3K pathways effectively blocks the progression of KRAS‐mutated colorectal cancer cells

et al. 2021

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Mutated KRAS promotes the activation of the MAPK pathway and the progression of colorectal cancer (CRC) cells. Aberrant activation of the PI3K pathway strongly attenuates the efficacy of MAPK suppression in KRAS‐mutated CRC. The development of a novel strategy targeting a dual pathway is therefore highly essential for the therapy of KRAS‐mutated CRC. In this study, a quadruple‐depleting system for the KRAS, MEK1, PIK3CA, and MTOR genes based on CRISPR/SaCas9 was developed. Adenovirus serotype 5 (ADV5) was integrated with two engineered proteins, an adaptor and a protector, to form ADV‐protein complex (APC) for systemic delivery of the CRISPR system. Quadruple‐editing could significantly inhibit the MAPK and PI3K pathways in CRC cells with oncogenic mutations of KRAS and PIK3CA or with KRAS mutation and compensated PI3K activation. Compared with MEK and PI3K/MTOR inhibitors, quadruple‐editing induced more significant survival inhibition on primary CRC cells with oncogenic mutations of KRAS and PIK3CA. The adaptor specifically targeting EpCAM and the hexon‐shielding protector could dramatically enhance ADV5 infection efficiency to CRC cells and significantly reduce off‐targeting tropisms to many organs except the colon. Moreover, quadruple‐editing intravenously delivered by APC significantly blocked the dual pathway and tumor growth of KRAS‐mutated CRC cells, without influencing normal tissues in cell‐ and patient‐derived xenograft models. Therefore, APC‐delivered quadruple‐editing of the MAPK and PI3K pathways shows a promising therapeutic potential for KRAS‐mutated CRC.

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Section: Discussionmentioning

confidence: 62%

Quadruple‐editing of the MAPK and PI3K pathways effectively blocks the progression of KRAS‐mutated colorectal cancer cells

et al. 2021

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“…Patients received combined regimens including BRAF and MEK inhibitors presented a prolonged overall survival than the control group in a BRAF V600E mutated CRC clinical trial [33]. For PI3K pathway, dual inhibitors of PI3K/MTOR displayed a stronger effect than MTOR inhibitor alone in not only hematological tumors but also solid tumors [34][35][36]. Furthermore, based on our data, simultaneously depleting KRAS/MEK1 and PIK3CA/MTOR respectively inhibited the signaling of MAPK and PI3K, more signi cantly than individual depletions, revealed by the extents of down-regulation of phosphorylated ERK and S6K (Figure 2C-2D, 3C-3D).…”

Section: Discussionmentioning

confidence: 99%

Quadruple-editing of MAPK and PI3K pathways effectively blocks the progression of KRAS-mutated colorectal cancer cells

Wang

Kang

Gao

et al. 2021

Preprint

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Background Mutated KRAS promotes the activation of mitogen-activated protein kinase (MAPK) pathway and the progression of colorectal cancer (CRC) cells. Aberrant activation of phosphatidylinositol 3‑kinase (PI3K) pathway strongly attenuates the efficacy of MAPK suppression in KRAS-mutated CRC cells. The development of a novel strategy targeting dual-pathway is therefore highly essential for the therapy of KRAS-mutated CRC cells. Methods In this study, a quadruple-depleting system for KRAS, MEK1, PIK3CA, and mammalian target of rapamycin (MTOR) genes based on Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)/SaCas9 was developed. Serotype 5 of adenovirus (ADV5) was used as packaging virus for systemic delivery of the CRISPR system. To enhance infection efficiency and specificity of ADV5 to CRC cells and reduce its non-specific tissue tropism, two engineered proteins, an adaptor and a protector were synthesized and formed an ADV-protein complex (APC) when delivered the quadruple-editing system intravenously in vivo. Results The quadruple-editing significantly inhibited MAPK and PI3K pathways in CRC cells with oncogenic mutations of KRAS and PIK3CA or with KRAS mutation and compensated PI3K activation. Compared with MEK and PI3K/MTOR inhibitors, the quadruple-editing induced more significant survival inhibition on primary CRC cells with oncogenic mutations of KRAS and PIK3CA. The adaptor protein which specifically targeting epithelial cell adhesion molecule (EpCAM) could dramatically enhance infection efficiency of ADV5 to CRC cells. and the protector protein could significantly reduce the off-targeting tropisms in a variety of organs. Moreover, the quadruple-editing intravenously delivered by APC significantly blocked dual-pathway and tumor growth, without influencing normal tissues in cell- and patient-derived xenograft models of KRAS-mutated CRC cells. Conclusions APC-delivered quadruple-editing of MAPK and PI3K pathways effectively and specifically blocked the progression of KRAS-mutated CRC cells.

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“…Nude mice are transplanted efficiently with MF cells (Bresin et al, 2020;Chen et al, 2009;Frei et al, 2008;Kremer et al, 2010;Ku ¨nzi et al, 2006;Li et al, 2020;Thaler et al, 2004;Tun-Kyi et al, 2008;Yano et al, 2007). SS cells require more immunocompromised mice such as SCID or the SCID beige variant (Chang et al, 2012;Charley et al, 1990;Doebbeling, 2010;Han et al, 2012;Rosenblatt-Velin et al, 1997;Shao et al, 2010;Yano et al, 2007), NOD/SCID (Esmailzadeh et al, 2015;Han et al, 2018;Kamijo et al, 2018;Kato et al, 2016;Wang et al, 2018), NOG/NSG (Horwitz et al, 2018;Ito et al, 2009;Jain et al, 2015;Ng et al, 2018;Okada et al, 2019;Wu et al, 2014Wu et al, , 2015, or NOD/SCID-B2m -/- (Krejsgaard et al, 2010;Petersen et al, 2014;Ralfkiaer et al, 2011).…”

Section: Xenograft Mouse Modelmentioning

confidence: 99%

“…Kinase inhibitors have been extensively studied for MF/SS therapy through the xenograft model (Gallardo et al, 2018;Kittipongdaja et al, 2015;Kremer et al, 2010;Petersen et al, 2014;Wang et al, 2018;Zhang et al, 2018). Recently, we have shown the therapeutic potential of phosphoinositide 3kinase (PI3K)/mTOR dual inhibitors in MF/SS on HH cells transplanted into nude mice (Bresin et al, 2020), with enhanced apoptosis induction in vivo but not in vitro.…”

Section: Xenograft Mouse Modelmentioning

confidence: 99%

Challenging Cutaneous T-Cell Lymphoma: What Animal Models Tell us So Far

Bresin

Caprini

Russo

et al. 2022

Journal of Investigative Dermatology

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Cutaneous T-cell lymphomas are characterized by heterogeneity of clinical variants, further complicated by genomic and microenvironmental variables. Furthermore, in vitro experiments are hampered by the low culture efficiency of these malignant cells. Animal models are essential for understanding the pathogenetic mechanisms underlying malignancy and for discovering new anticancer treatments. They are divided into two main categories: those in which tumors arise in the host owing to genetic modifications and those that use tumor cell transplantation. In this review, we summarize the attempts to decipher the complexity of the pathogenesis of cutaneous T-cell lymphoma by exploiting genetically modified and xenograft models.

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Preclinical Evidence for Targeting PI3K/mTOR Signaling with Dual-Inhibitors as a Therapeutic Strategy against Cutaneous T-Cell Lymphoma

Cited by 23 publications

References 59 publications

Quadruple‐editing of the MAPK and PI3K pathways effectively blocks the progression of KRAS‐mutated colorectal cancer cells

Quadruple‐editing of the MAPK and PI3K pathways effectively blocks the progression of KRAS‐mutated colorectal cancer cells

Quadruple-editing of MAPK and PI3K pathways effectively blocks the progression of KRAS-mutated colorectal cancer cells

Challenging Cutaneous T-Cell Lymphoma: What Animal Models Tell us So Far

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