A Kinase Inhibitor Targeted to mTORC1 Drives Regression in Glioblastoma

Fan, Qi-Wen; Aksoy, Ozlem; Wong, Robyn A.; Ilkhanizadeh, Shirin; Novotny, Chris J.; Gustafson, W. Clay; Truong, Albert; Cayanan, Geraldine; Simonds, Erin F.; Haas‐Kogan, Daphne A.; Phillips, Joanna J.; Nicolaides, Theodore; Okaniwa, Masanori; Weiss, William A.

doi:10.1016/j.ccell.2017.01.014

Cited by 147 publications

(149 citation statements)

References 28 publications

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“…Thus, the RapaLink design may more effectively delay the acquisition of mTOR resistance mechanisms. A follow up study highlighted two additional advantages of RapaLinks compared to TORKi (Fan et al, 2017). First, RapaLinks are somewhat selective for mTORC1 versus mTORC2 (Figure 2), possibly reducing toxicities associated with mTORC2 inhibition.…”

Section: Therapeutic Targeting Of the Pi3k Pathway In Cancermentioning

confidence: 99%

The PI3K Pathway in Human Disease

Fruman

Chiu

Hopkins

et al. 2017

Cell

1,967

1,658

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Phosphoinositide 3-kinase (PI3K) activity is stimulated by diverse oncogenes and growth factor receptors, and elevated PI3K signaling is considered a hallmark of cancer. Many PI3K pathway-targeted therapies have been tested in oncology trials, resulting in regulatory approval of one isoform-selective inhibitor (idelalisib) for treatment of certain blood cancers, and a variety of other agents at different stages of development. In parallel to PI3K research by cancer biologists, investigations in other fields have uncovered exciting and often unpredicted roles for PI3K catalytic and regulatory subunits in normal cell function and in disease. Many of these functions impinge upon oncology by influencing the efficacy and toxicity of PI3K-targeted therapies. Here we provide a perspective on the roles of class I PI3Ks in the regulation of cellular metabolism and in immune system functions, two topics closely intertwined with cancer biology. We also discuss recent progress developing PI3K-targeted therapies for treatment of cancer and other diseases.

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Section: Therapeutic Targeting Of the Pi3k Pathway In Cancermentioning

confidence: 99%

The PI3K Pathway in Human Disease

Fruman

Chiu

Hopkins

et al. 2017

Cell

1,967

1,658

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“…As expected, following mTOR deletion, PreT-OPC reactivation is unaffected but malignant transformation is completely blocked. Encouragingly, very recently a new class of mTOR inhibitor that can effectively penetrate BBB and inhibit mTOR kinase activity was found to have significant anti-tumor effects on glioma cells (Fan et al, 2017). One conceivable explanation is that, since mTOR KO is restricted to OPCs while the drug works on all cell types, the inhibition of OPC reactivation by the drug could go through non-cell autonomous mechanisms.…”

Section: Discussionmentioning

confidence: 99%

“…Clinically, while past trials with mTOR inhibitors for glioma patients showed limited efficacy, further studies demonstrated that most of these failures were caused by the inability of the drugs to effectively penetrate the blood-brain barrier (BBB) or to adequately inhibit their targets (Cloughesy et al, 2008;Rodrik-Outmezguine et al, 2016). Encouragingly, very recently a new class of mTOR inhibitor that can effectively penetrate BBB and inhibit mTOR kinase activity was found to have significant anti-tumor effects on glioma cells (Fan et al, 2017). Our data echo well with these findings and the existing knowledge of mTOR's critical role in OPC development (Guardiola-Diaz, Ishii, & Bansal, 2012), thus provide strong rationales for further testing of mTOR inhibitors in glioma patients.…”

Section: Discussionmentioning

confidence: 99%

p53 and NF 1 loss plays distinct but complementary roles in glioma initiation and progression

Gonzalez

Kim

Galvão

et al. 2018

Glia

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Malignant glioma is one of the deadliest types of cancer. Understanding how the cell of origin progressively evolves toward malignancy in greater detail could provide mechanistic insights and lead to novel concepts for tumor prevention and therapy. Previously we have identified oligodendrocyte precursor cell (OPC) as the cell of origin for glioma following the concurrent deletion of p53 and NF1 using a mouse genetic mosaic system that can reveal mutant cells prior to malignancy. In the current study, we set out to deconstruct the gliomagenic process in two aspects. First, we determined how the individual loss of p53 or NF1 contributes to aberrant behaviors of OPCs. Second, we determined how signaling aberrations in OPCs progressively change from pre-malignant to transformed stages. We found that while the deletion of NF1 leads to mutant OPC expansion through increased proliferation and decreased differentiation, the deletion of p53 impairs OPC senescence. Signaling analysis showed that, while PI3K and MEK pathways go through stepwise over-activation, mTOR signaling remains at the basal level in pre-transforming mutant OPCs but is abruptly up-regulated in tumor OPCs. Finally, inhibiting mTOR via pharmacological or genetic methods, led to a significant blockade of gliomagenesis but had little impact on pre-transforming mutant OPCs, suggesting that mTOR is necessary for final transformation but not early progression. In summary, our findings show that deconstructing the tumorigenic process reveals specific aberrations caused by individual gene mutations and altered signaling events at precise timing during tumor progression, which may shed light on tumor-prevention strategies.

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“…B, Schematic diagrams illustrating how allosteric driver mutations release autoinhibition. For this reason, reversing it by allosteric noncovalent [147][148][149] and covalent 150,151 drugs is also a formidable pharmacological task. Allosteric inhibitors require the autoinhibited conformation.…”

Section: Conclusion: Are Autoinhibited States Good Targets For Drumentioning

confidence: 99%

Autoinhibition can identify rare driver mutations and advise pharmacology

2019

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Identification of protein mutations that drive cancer is a major challenge. A primary reason is that driver mutations are principally identified by their high frequency even though they can also be rare. Driver mutations can locate at functional (binding or active) sites. We dub these orthosteric drivers. However, often they are allosteric drivers. Identification is particularly formidable for rare allosteric drivers. Autoinhibition, where a segment of the protein covers its functional site, is a common allosteric regulation mechanism. A modest shift in the equilibrium can switch the system from the autoinhibited to the active state. This can suggest why (i) mutations are likely to evolve to target it; (ii) inhibitors can straightforwardly relieve the autoinhibition but not vice versa; and why (iii) mutations that relieve the autoinhibition are likely to be drivers—even if they are rare. We explain in simple terms the linkage between allosteric driver mutations, release of autoinhibition, free energy landscapes, and targeted pharmacology in precision medicine. We review the literature and propose new concepts in identification of rare drivers in this framework.

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A Kinase Inhibitor Targeted to mTORC1 Drives Regression in Glioblastoma

Cited by 147 publications

References 28 publications

The PI3K Pathway in Human Disease

The PI3K Pathway in Human Disease

p53 and NF 1 loss plays distinct but complementary roles in glioma initiation and progression

Autoinhibition can identify rare driver mutations and advise pharmacology

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