Landscape of Phosphatidylinositol-3-Kinase Pathway Alterations Across 19 784 Diverse Solid Tumors

Millis, Sherri Z.; Ikeda, Sadakatsu; Reddy, Sandeep; Gatalica, Zoran; Kurzrock, Razelle

doi:10.1001/jamaoncol.2016.0891

Cited by 212 publications

(173 citation statements)

References 70 publications

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“…4 The terminology "aberrant muscle syndrome" or "accessory muscle syndrome" has been suggested to describe patients with "hypertrophy of the hand and arm because of aberrant muscles with or without hypertrophy of the muscles." 1,[9][10][11] Previous studies show that the same PIK3CA hotspot mutations found in cancer are found in PROS. 6 The etiology remains still undetermined but it has recently been reported that isolated congenital muscular upper limb overgrowth can be related to somatic mosaic PIK3CA mutations.…”

Section: Introductionmentioning

confidence: 81%

Early activating somatic PIK3CA mutations promote ectopic muscle development and upper limb overgrowth

et al. 2019

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PIK3CA-related overgrowth spectrum is a group of rare genetic disorders with asymmetric overgrowth caused by somatic mosaic PIK3CA mutations. Here, we report clinical data and molecular findings from two patients with congenital muscular upper limb overgrowth and aberrant anatomy. During debulking surgery, numerous ectopic muscles were found in the upper limbs of the patients. DNA sequencing, followed by digital polymerase chain reaction, was performed on DNA extracted from biopsies from hypertrophic ectopic muscles and identified the somatic mosaic PIK3CA hotspot mutations c.3140A > G, p.(His1047Arg) and c.1624G > A, p.(Glu542Lys) in a male (patient 1) and a female (patient 2) patient, respectively. Patient 1 had four ectopic muscles and unilateral isolated muscular overgrowth while patient 2 had 13 ectopic muscles and bilateral isolated muscular overgrowth of both upper limbs, indicating that her mutation occurred at early pre-somitic mesoderm state. The finding of PIK3CA mutations in ectopic muscles highlights the importance of PIK3CA in cell fate in early human embryonic development. Moreover, our findings provide evidence that the disease phenotype depends on the timing of PIK3CA mutagenesis during embryogenesis and confirm the diagnostic entity PIK3CA-related muscular overgrowth with ectopic accessory muscles. K E Y W O R D Saccessory, cell fate, ectopic, muscle hypertrophy, muscular hypertrophy, PIK3CA, PROS Tobias Laurell and Ann Nordgren contributed equally.

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Section: Introductionmentioning

confidence: 81%

Early activating somatic PIK3CA mutations promote ectopic muscle development and upper limb overgrowth

et al. 2019

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“…Activation of PI3K signaling through a variety of mechanisms, including PIK3CA activating mutations or amplification, and PTEN mutation, deletion or silencing, is found in about 40% of all human cancers (1,2). Some specific tumor types, such as breast, prostate, colorectal, and endometrial cancer, as well as glioblastoma and anaplastic thyroid carcinoma, show even higher mutation rates for members of this pathway (2,3).…”

Section: Introductionmentioning

confidence: 99%

“…Some specific tumor types, such as breast, prostate, colorectal, and endometrial cancer, as well as glioblastoma and anaplastic thyroid carcinoma, show even higher mutation rates for members of this pathway (2,3). PI3K-dependent generation of phosphatidylinositol-3,4,5-triphosphate (PIP3) triggers membrane recruitment of proteins containing a PH-domain, such as the three AKT isoforms and the PDK1 kinase.…”

Section: Introductionmentioning

confidence: 99%

SGK1 Is a Critical Component of an AKT-Independent Pathway Essential for PI3K-Mediated Tumor Development and Maintenance

et al. 2017

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Activation of the PI3K-AKT signaling cascade is a common critical event during malignant transformation. In this study, we used thyroid gland epithelial cells and a series of genetically engineered mouse strains as model systems to demonstrate that, while necessary, AKT activation is not sufficient for PI3K-driven transformation. Instead, transformation requires the activity of the PDK1-regulated AGC family of protein kinases. In particular, SGK1 was found to be essential for proliferation and survival of thyroid cancer cells harboring PI3K-activating mutations. Notably, co-targeting SGK1 and AKT resulted in significantly higher growth suppression than inhibiting either PI3K or AKT alone. Overall, these findings underscore the clinical relevance of AKT-independent pathways in tumors driven by genetic lesions targeting the PI3K cascade.

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“…[116][117][118][119] Comprehensive atomic-scale simulations were able to unveil the mechanisms of some oncogenic mutations. [116][117][118][119] Comprehensive atomic-scale simulations were able to unveil the mechanisms of some oncogenic mutations.…”

Section: Autoinhibition Is a Common Target Of Allosteric Driver Mutmentioning

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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Landscape of Phosphatidylinositol-3-Kinase Pathway Alterations Across 19 784 Diverse Solid Tumors

Abstract: PI3K pathway aberrations are among the most common in cancer. They do not segregate by classic cancer histologic characteristics. Patterns of biomarker coalterations involving HER2 and hormone receptors may be important for optimizing combination treatments across cancer types.

Cited by 212 publications

References 70 publications

Early activating somatic PIK3CA mutations promote ectopic muscle development and upper limb overgrowth

Early activating somatic PIK3CA mutations promote ectopic muscle development and upper limb overgrowth

SGK1 Is a Critical Component of an AKT-Independent Pathway Essential for PI3K-Mediated Tumor Development and Maintenance

Autoinhibition can identify rare driver mutations and advise pharmacology

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Landscape of Phosphatidylinositol-3-Kinase Pathway Alterations Across 19 784 Diverse Solid Tumors

Abstract: PI3K pathway aberrations are among the most common in cancer. They do not segregate by classic cancer histologic characteristics. Patterns of biomarker coalterations involving HER2 and hormone receptors may be important for optimizing combination treatments across cancer types.

Cited by 212 publications

References 70 publications

Early activating somatic PIK3CA mutations promote ectopic muscle development and upper limb overgrowth

Early activating somatic PIK3CA mutations promote ectopic muscle development and upper limb overgrowth

SGK1 Is a Critical Component of an AKT-Independent Pathway Essential for PI3K-Mediated Tumor Development and Maintenance

Autoinhibition can identify rare driver mutations and advise pharmacology

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Landscape of Phosphatidylinositol-3-Kinase Pathway Alterations Across 19 784 Diverse Solid Tumors