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Lydia W T Cheung - One of the best experts on this subject based on the ideXlab platform.
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Deregulated Gab2 phosphorylation mediates aberrant AKT and STAT3 signaling upon PIK3R1 loss in ovarian cancer.
Nature communications, 2019Co-Authors: Victor C.y. Mak, Yuan Zhou, Annie N.y. Cheung, Gordon B. Mills, Chao Wang, Esther S Y Wong, Rakesh Sharma, Lydia W T CheungAbstract:Copy number loss of PIK3R1 (p85α) most commonly occurs in ovarian cancer among all cancer types. Here we report that ovarian cancer cells manifest a spectrum of tumorigenic phenotypes upon knockdown of PIK3R1. PIK3R1 loss activates AKT and p110-independent JAK2/STAT3 signaling through inducing changes in the phosphorylation of the docking protein Gab2, thereby relieving the negative inhibition on AKT and promoting the assembly of JAK2/STAT3 signalosome, respectively. Additional mechanisms leading to AKT activation include enhanced p110α kinase activity and a decrease in PTEN level. PIK3R1 loss renders ovarian cancer cells vulnerable to inhibition of AKT or JAK2/STAT3. The combination of AKT and STAT3 inhibitors significantly increases the anti-tumor effect compared to single-agent treatments. Together, our findings provide a rationale for mechanism-based therapeutic approach that targets tumors with loss of PIK3R1.
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PIK3R1 loss activates AKT and STAT3 signaling in ovarian cancer
Experimental and Molecular Therapeutics, 2018Co-Authors: Victor C.y. Mak, Yuan Zhou, Annie N.y. Cheung, Gordon B. Mills, Lydia W T CheungAbstract:The phosphoinositide 3-kinase (PI3K) regulatory subunit p85α is one of the critical gatekeepers of PI3K pathway activation through stabilizing and inhibiting the catalytic subunit p110. p85α is encoded by PIK3R1, which is frequently mutated or deleted in multiple cancer types including ovarian cancer, providing justification of exploring the approaches to target the aberrations. In this study, we observed a spectrum of oncogenic phenotypes in ovarian cancer cells upon knockdown of PIK3R1 in vitro and in vivo, indicating the functional significance of PIK3R1 loss in ovarian cancer. Strikingly, PIK3R1 loss not only led to AKT activation (canonical signaling of PI3K), but also unexpectedly JAK2/STAT3 signaling activation (non-canonical signaling of PI3K). PIK3R1 loss induced translocation of STAT3 into the nucleus, where gene transcription was promoted and thereby the malignant properties. Using in vitro 3D culture spheroid assay, we found that PIK3R1 loss sensitized ovarian cancer cells to AKT inhibitors and JAK2/STAT3 inhibitors. More importantly, the combination of AKT and STAT3 inhibitors resulted in synergistic loss of cell viability. The demonstrated signaling alterations and the associated therapeutic susceptibility downstream of PIK3R1 loss may open new avenue for the treatment of PIK3R1 loss-bearing cancer. [This study was supported by Research Grants Council of the Hong Kong SAR, China, Project No. 27103616] Citation Format: Xinran LI, Victor CY Mak, Yuan Zhou, Yiling Lu, Annie NY Cheung, Gordon B Mills, Lydia WT Cheung. PIK3R1 loss activates AKT and STAT3 signaling in ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3955.
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Targeting therapeutic liabilities engendered by PIK3R1 mutations for cancer treatment
Pharmacogenomics, 2016Co-Authors: Lydia W T Cheung, Gordon B. MillsAbstract:The regulatory subunit of PI3K, p85α (encoded by PIK3R1), binds, stabilizes and inhibits the PI3K p110 catalytic subunit. Functional characterization of PIK3R1 mutations has identified not only hypomorphs with reduced inhibition of p110, but also hypomorphs and dominant negative mutants that disrupt a novel regulatory role of p85α on PTEN or neomorphs that activate unexpected signaling pathways. The diverse phenotypic spectrum of these PIK3R1 driver mutations underscores the need for different treatment strategies targeting tumors harboring these mutations. This article describes the functional consequences of the spectrum of PIK3R1 driver mutations and therapeutic liabilities they may engender.
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Naturally occurring neomorphic PIK3R1 mutations activate the MAPK pathway, dictating therapeutic response to MAPK pathway inhibitors.
Cancer cell, 2014Co-Authors: Lydia W T Cheung, Dong Zhang, Nattapon Panupinthu, Shreya Mitra, Han LiangAbstract:Summary PIK3R1 (p85α regulatory subunit of PI3K) is frequently mutated across cancer lineages. Herein, we demonstrate that the most common recurrent PIK3R1 mutation PIK3R1 R348∗ and a nearby mutation PIK3R1 L370fs , in contrast to wild-type and mutations in other regions of PIK3R1 , confers an unexpected sensitivity to MEK and JNK inhibitors in vitro and in vivo. Consistent with the response to inhibitors, PIK3R1 R348∗ and PIK3R1 L370fs unexpectedly increase JNK and ERK phosphorylation. Surprisingly, p85α R348 ∗ and L370fs localize to the nucleus where the mutants provide a scaffold for multiple JNK pathway components facilitating nuclear JNK pathway activation. Our findings uncover an unexpected neomorphic role for PIK3R1 R348∗ and neighboring truncation mutations in cellular signaling, providing a rationale for therapeutic targeting of these mutant tumors.
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Somatic Mutations of PIK3R1 Promote Gliomagenesis
PloS one, 2012Co-Authors: Steven N. Quayle, Lydia W T Cheung, Jennifer Y. Lee, Li Ding, Ruprecht Wiedemeyer, Robert W. Dewan, Emmet Huang-hobbs, Li Zhuang, Richard Wilson, Keith L. LigonAbstract:The phosphoinositide 3-kinase (PI3K) pathway is targeted for frequent alteration in glioblastoma (GBM) and is one of the core GBM pathways defined by The Cancer Genome Atlas. Somatic mutations of PIK3R1 are observed in multiple tumor types, but the tumorigenic activity of these mutations has not been demonstrated in GBM. We show here that somatic mutations in the iSH2 domain of PIK3R1 act as oncogenic driver events. Specifically, introduction of a subset of the mutations identified in human GBM, in the nSH2 and iSH2 domains, increases signaling through the PI3K pathway and promotes tumorigenesis of primary normal human astrocytes in an orthotopic xenograft model. Furthermore, we show that cells that are dependent on mutant P85α-mediated PI3K signaling exhibit increased sensitivity to a small molecule inhibitor of AKT. Together, these results suggest that GBM patients whose tumors carry mutant PIK3R1 alleles may benefit from treatment with inhibitors of AKT.
Melody A. Cobleigh - One of the best experts on this subject based on the ideXlab platform.
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Somatic loss of PIK3R1 may sensitize breast cancer to inhibitors of the MAPK pathway
Breast Cancer Research and Treatment, 2019Co-Authors: Sanja B. Turturro, Abde M. Abukhdeir, Matthew S. Najor, Timothy Yung, Liam Portt, Christopher S. Malarkey, Melody A. CobleighAbstract:Purpose The PI3K pathway, which includes the PI3K catalytic subunits p110α (PIK3CA) and the PI3K regulatory subunit p85α (PIK3R1), is the most frequently altered pathway in cancer. We encountered a breast cancer patient whose tumor contained a somatic alteration in PIK3R1. Some commercial sequencing platforms suggest that somatic mutations in PIK3R1 may sensitize cancers to drugs that inhibit the mammalian target of rapamycin (mTOR). However, a review of the preclinical and clinical literature did not find evidence substantiating that hypothesis. The purpose of this study was to knock out PIK3R1 in order to determine the optimal therapeutic approach for breast cancers lacking p85α. Methods We created an isogenic cellular system by knocking out both alleles of the PIK3R1 gene in the non-tumorigenic human breast cell line MCF-10A. Knockout cells were compared with wild-type cells by measuring growth, cellular signaling, and response to drugs. Results We observed hyperphosphorylation of MEK in these knockouts, which sensitized PIK3R1-null cells to a MEK inhibitor, trametinib. However, they were not sensitized to the mTOR inhibitor, everolimus. Conclusions Our findings suggest that breast cancers with loss of p85α may not respond to mTOR inhibition, but may be sensitive to MEK inhibition.
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Somatic loss of PIK3R1 may sensitize breast cancer to inhibitors of the MAPK pathway.
Breast cancer research and treatment, 2019Co-Authors: Sanja Turturro, Abde M. Abukhdeir, Matthew S. Najor, Timothy Yung, Liam Portt, Christopher S. Malarkey, Melody A. CobleighAbstract:The PI3K pathway, which includes the PI3K catalytic subunits p110α (PIK3CA) and the PI3K regulatory subunit p85α (PIK3R1), is the most frequently altered pathway in cancer. We encountered a breast cancer patient whose tumor contained a somatic alteration in PIK3R1. Some commercial sequencing platforms suggest that somatic mutations in PIK3R1 may sensitize cancers to drugs that inhibit the mammalian target of rapamycin (mTOR). However, a review of the preclinical and clinical literature did not find evidence substantiating that hypothesis. The purpose of this study was to knock out PIK3R1 in order to determine the optimal therapeutic approach for breast cancers lacking p85α. We created an isogenic cellular system by knocking out both alleles of the PIK3R1 gene in the non-tumorigenic human breast cell line MCF-10A. Knockout cells were compared with wild-type cells by measuring growth, cellular signaling, and response to drugs. We observed hyperphosphorylation of MEK in these knockouts, which sensitized PIK3R1-null cells to a MEK inhibitor, trametinib. However, they were not sensitized to the mTOR inhibitor, everolimus. Our findings suggest that breast cancers with loss of p85α may not respond to mTOR inhibition, but may be sensitive to MEK inhibition.
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Abstract P6-11-17: Mutations in PIK3R1 activate multiple pathways in breast cancer
Poster Session Abstracts, 2017Co-Authors: Abde M. Abukhdeir, Sanja Turturro, Najor, Satnam Brar, Melody A. CobleighAbstract:It has been estimated that by the end of this year, 270,000 American women will be newly diagnosed with breast cancer, while 40,000 women that already have breast cancer will succumb to the disease. Considerable attention has been given to the PI3K signaling cascade following the discovery that PIK3CA is the most frequently mutated oncogene in breast cancer.However, few studies have explored the function of PIK3R1, which is the regulatory domain of the PI3K complex, despite being mutated in ~3% of all breast cancers. Several studies have demonstrated that expression of PIK3R1 is downregulated in human cancers. Decreased expression of the PIK3R1 protein leads to tumor formation, suggesting its role as a tumor suppressor gene and a potential prognostic marker in breast cancer. However, PIK3R1 is a gene with little pre-clinical evidence to recommend experimental therapies. Despite this lack of evidence, commercial services that perform molecular analyses of tumors suggest the use of an mTOR inhibitor for patients whose breast cancers carry mutant PIK3R1. In order to determine if mTOR inhibitors were indeed effective in mutant PIK3R1 tumors, we created and characterized a model for mutant PIK3R1 in the non-tumorigenic, human breast epithelial cell line, MCF-10A. Surprisingly, we observed that mTOR inhibitors were ineffective in these cells. However, in searching for other classes of small molecule inhibitors that were effective, we observed that mutations in PIK3R1 sensitized cells to MAPK inhibitors. Herein, we present the first evidence for the use of targeted therapies in breast cancers carrying mutant PIK3R1. We provide evidence against the use of mTOR inhibitors and provide a rationale for the use of MAPK inhibitors. Citation Format: Abukhdeir AM, Turturro SB, Najor MS, Brar SS, Cobleigh MA. Mutations in PIK3R1 activate multiple pathways in breast cancer [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P6-11-17.
Philip E Thorpe - One of the best experts on this subject based on the ideXlab platform.
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organ specific lymphangiectasia arrested lymphatic sprouting and maturation defects resulting from gene targeting of the pi3k regulatory isoforms p85α p55α and p50α
Developmental Dynamics, 2009Co-Authors: Carla Moutabellum, Aleksander Kirov, Laura Micelilibby, Maria Cecilia Mancini, Tatiana Petrova, Lucy Liaw, Igor Prudovsky, Philip E ThorpeAbstract:The phosphoinositide 3-kinase (PI3K) family has multiple vascular functions, but the specific regulatory isoform supporting lymphangiogenesis remains unidentified. Here, we report that deletion of the PIK3R1 gene, encoding the regulatory subunits p85α, p55α, and p50α impairs lymphatic sprouting and maturation, and causes abnormal lymphatic morphology, without major impact on blood vessels. PIK3R1 deletion had the most severe consequences among gut and diaphragm lymphatics, which share the retroperitoneal anlage, initially suggesting that the PIK3R1 role in this vasculature is anlage-dependent. However, whereas lymphatic sprouting toward the diaphragm was arrested, lymphatics invaded the gut, where remodeling and valve formation were impaired. Thus, cell-origin fails to explain the phenotype. Only the gut showed lymphangiectasia, lymphatic up-regulation of the transforming growth factor-β co-receptor endoglin, and reduced levels of mature vascular endothelial growth factor-C protein. Our data suggest that PIK3R1 isoforms are required for distinct steps of embryonic lymphangiogenesis in different organ microenvironments, whereas they are largely dispensable for hemangiogenesis. Developmental Dynamics 238:2670–2679, 2009. © 2009 Wiley-Liss, Inc.
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Organ‐specific lymphangiectasia, arrested lymphatic sprouting, and maturation defects resulting from gene‐targeting of the PI3K regulatory isoforms p85α, p55α, and p50α
Developmental dynamics : an official publication of the American Association of Anatomists, 2009Co-Authors: Carla Mouta-bellum, Aleksander Kirov, Maria Cecilia Mancini, Tatiana Petrova, Lucy Liaw, Igor Prudovsky, Philip E Thorpe, Laura Miceli-libby, Naoyuki Miura, Lewis C CantleyAbstract:The phosphoinositide 3-kinase (PI3K) family has multiple vascular functions, but the specific regulatory isoform supporting lymphangiogenesis remains unidentified. Here, we report that deletion of the PIK3R1 gene, encoding the regulatory subunits p85α, p55α, and p50α impairs lymphatic sprouting and maturation, and causes abnormal lymphatic morphology, without major impact on blood vessels. PIK3R1 deletion had the most severe consequences among gut and diaphragm lymphatics, which share the retroperitoneal anlage, initially suggesting that the PIK3R1 role in this vasculature is anlage-dependent. However, whereas lymphatic sprouting toward the diaphragm was arrested, lymphatics invaded the gut, where remodeling and valve formation were impaired. Thus, cell-origin fails to explain the phenotype. Only the gut showed lymphangiectasia, lymphatic up-regulation of the transforming growth factor-β co-receptor endoglin, and reduced levels of mature vascular endothelial growth factor-C protein. Our data suggest that PIK3R1 isoforms are required for distinct steps of embryonic lymphangiogenesis in different organ microenvironments, whereas they are largely dispensable for hemangiogenesis. Developmental Dynamics 238:2670–2679, 2009. © 2009 Wiley-Liss, Inc.
Lewis C Cantley - One of the best experts on this subject based on the ideXlab platform.
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PI3K-p110α mediates the oncogenic activity induced by loss of the novel tumor suppressor PI3K-p85α.
Proceedings of the National Academy of Sciences of the United States of America, 2017Co-Authors: Lauren M. Thorpe, Lewis C Cantley, Jennifer M. Spangle, Carolynn E. Ohlson, Hailing Cheng, Thomas M. Roberts, Jean J. ZhaoAbstract:Mutation or loss of the p85 regulatory subunit of phosphatidylinositol 3-kinase (PI3K) is emerging as a transforming factor in cancer, but the mechanism of transformation has been controversial. Here we find that hemizygous deletion of the PIK3R1 gene encoding p85α is a frequent event in breast cancer, with PIK3R1 expression significantly reduced in breast tumors. PIK3R1 knockdown transforms human mammary epithelial cells, and genetic ablation of PIK3R1 accelerates a mouse model of HER2/neu-driven breast cancer. We demonstrate that partial loss of p85α increases the amount of p110α-p85 heterodimers bound to active receptors, augmenting PI3K signaling and oncogenic transformation. Pan-PI3K and p110α-selective pharmacological inhibition effectively blocks transformation driven by partial p85α loss both in vitro and in vivo. Together, our data suggest that p85α plays a tumor-suppressive role in transformation, and suggest that p110α-selective therapeutics may be effective in the treatment of breast cancer patients with PIK3R1 loss.
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high frequency of PIK3R1 and pik3r2 mutations in endometrial cancer elucidates a novel mechanism for regulation of pten protein stability
Cancer Discovery, 2011Co-Authors: Lydia W T Cheung, Bryan T Hennessy, Andrea P Myers, Bojana Djordjevic, Katherine Stemkehale, Mary D Dyer, Fan Zhang, Lewis C Cantley, Steven E SchererAbstract:We demonstrate that phosphatidylinositol 3-kinase (PI3K) pathway aberrations occur in >80% of endometrioid endometrial cancers, with coordinate mutations of multiple PI3K pathway members being more common than predicted by chance. PIK3R1 (p85α) mutations occur at a higher rate in endometrial cancer than in any other tumor lineage, and PIK3R2 (p85β), not previously demonstrated to be a cancer gene, is also frequently mutated. The dominant activation event in the PI3K pathway appears to be PTEN protein loss. However, in tumors with retained PTEN protein, PI3K pathway mutations phenocopy PTEN loss, resulting in pathway activation. KRAS mutations are common in endometrioid tumors activating independent events from PI3K pathway aberrations. Multiple PIK3R1 and PIK3R2 mutations demonstrate gain of function, including disruption of a novel mechanism of pathway regulation wherein p85α dimers bind and stabilize PTEN. Taken together, the PI3K pathway represents a critical driver of endometrial cancer pathogenesis and a novel therapeutic target.
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Organ‐specific lymphangiectasia, arrested lymphatic sprouting, and maturation defects resulting from gene‐targeting of the PI3K regulatory isoforms p85α, p55α, and p50α
Developmental dynamics : an official publication of the American Association of Anatomists, 2009Co-Authors: Carla Mouta-bellum, Aleksander Kirov, Maria Cecilia Mancini, Tatiana Petrova, Lucy Liaw, Igor Prudovsky, Philip E Thorpe, Laura Miceli-libby, Naoyuki Miura, Lewis C CantleyAbstract:The phosphoinositide 3-kinase (PI3K) family has multiple vascular functions, but the specific regulatory isoform supporting lymphangiogenesis remains unidentified. Here, we report that deletion of the PIK3R1 gene, encoding the regulatory subunits p85α, p55α, and p50α impairs lymphatic sprouting and maturation, and causes abnormal lymphatic morphology, without major impact on blood vessels. PIK3R1 deletion had the most severe consequences among gut and diaphragm lymphatics, which share the retroperitoneal anlage, initially suggesting that the PIK3R1 role in this vasculature is anlage-dependent. However, whereas lymphatic sprouting toward the diaphragm was arrested, lymphatics invaded the gut, where remodeling and valve formation were impaired. Thus, cell-origin fails to explain the phenotype. Only the gut showed lymphangiectasia, lymphatic up-regulation of the transforming growth factor-β co-receptor endoglin, and reduced levels of mature vascular endothelial growth factor-C protein. Our data suggest that PIK3R1 isoforms are required for distinct steps of embryonic lymphangiogenesis in different organ microenvironments, whereas they are largely dispensable for hemangiogenesis. Developmental Dynamics 238:2670–2679, 2009. © 2009 Wiley-Liss, Inc.
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divergent regulation of hepatic glucose and lipid metabolism by phosphoinositide 3 kinase via akt and pkcλ ζ
Cell Metabolism, 2006Co-Authors: Cullen M Taniguchi, Lewis C Cantley, Tatsuya Kondo, Mini P Sajan, Ji Luo, Roderick T Bronson, Tomoichiro Asano, Robert V Farese, Ronald C KahnAbstract:Summary Although the class I A phosphoinositide 3-kinase (PI3K) pathway is central to the metabolic actions of insulin, its mechanism of action is not well understood. To identify the role of the PI3K pathway in insulin regulation of hepatic function, we ablated the expression of both major regulatory subunits of PI3K by crossing mice lacking PIK3R1 in liver with Pik3r2 null mice, creating liver-specific double knockout mice (L-p85DKO). L-p85DKO mice failed to activate PI3K or generate PIP 3 upon insulin stimulation or activate its two major effectors, Akt and PKCλ/ξ. Decreased Akt activation resulted in increased gluconeogenic gene expression, impaired glucose tolerance, and hyperinsulinemia, while the defective activation of PKCλ/ξ by insulin was associated with hypolipidemia and decreased transcription of SREBP-1c. These data indicate that the PI3K pathway is critical for insulin's actions in the liver in vivo, and that differential regulation by Akt and PKCλ/ξ differentially defines specific actions of insulin and PI3K on hepatic glucose and lipid metabolism.
Gordon B. Mills - One of the best experts on this subject based on the ideXlab platform.
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Deregulated Gab2 phosphorylation mediates aberrant AKT and STAT3 signaling upon PIK3R1 loss in ovarian cancer.
Nature communications, 2019Co-Authors: Victor C.y. Mak, Yuan Zhou, Annie N.y. Cheung, Gordon B. Mills, Chao Wang, Esther S Y Wong, Rakesh Sharma, Lydia W T CheungAbstract:Copy number loss of PIK3R1 (p85α) most commonly occurs in ovarian cancer among all cancer types. Here we report that ovarian cancer cells manifest a spectrum of tumorigenic phenotypes upon knockdown of PIK3R1. PIK3R1 loss activates AKT and p110-independent JAK2/STAT3 signaling through inducing changes in the phosphorylation of the docking protein Gab2, thereby relieving the negative inhibition on AKT and promoting the assembly of JAK2/STAT3 signalosome, respectively. Additional mechanisms leading to AKT activation include enhanced p110α kinase activity and a decrease in PTEN level. PIK3R1 loss renders ovarian cancer cells vulnerable to inhibition of AKT or JAK2/STAT3. The combination of AKT and STAT3 inhibitors significantly increases the anti-tumor effect compared to single-agent treatments. Together, our findings provide a rationale for mechanism-based therapeutic approach that targets tumors with loss of PIK3R1.
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PIK3R1 loss activates AKT and STAT3 signaling in ovarian cancer
Experimental and Molecular Therapeutics, 2018Co-Authors: Victor C.y. Mak, Yuan Zhou, Annie N.y. Cheung, Gordon B. Mills, Lydia W T CheungAbstract:The phosphoinositide 3-kinase (PI3K) regulatory subunit p85α is one of the critical gatekeepers of PI3K pathway activation through stabilizing and inhibiting the catalytic subunit p110. p85α is encoded by PIK3R1, which is frequently mutated or deleted in multiple cancer types including ovarian cancer, providing justification of exploring the approaches to target the aberrations. In this study, we observed a spectrum of oncogenic phenotypes in ovarian cancer cells upon knockdown of PIK3R1 in vitro and in vivo, indicating the functional significance of PIK3R1 loss in ovarian cancer. Strikingly, PIK3R1 loss not only led to AKT activation (canonical signaling of PI3K), but also unexpectedly JAK2/STAT3 signaling activation (non-canonical signaling of PI3K). PIK3R1 loss induced translocation of STAT3 into the nucleus, where gene transcription was promoted and thereby the malignant properties. Using in vitro 3D culture spheroid assay, we found that PIK3R1 loss sensitized ovarian cancer cells to AKT inhibitors and JAK2/STAT3 inhibitors. More importantly, the combination of AKT and STAT3 inhibitors resulted in synergistic loss of cell viability. The demonstrated signaling alterations and the associated therapeutic susceptibility downstream of PIK3R1 loss may open new avenue for the treatment of PIK3R1 loss-bearing cancer. [This study was supported by Research Grants Council of the Hong Kong SAR, China, Project No. 27103616] Citation Format: Xinran LI, Victor CY Mak, Yuan Zhou, Yiling Lu, Annie NY Cheung, Gordon B Mills, Lydia WT Cheung. PIK3R1 loss activates AKT and STAT3 signaling in ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3955.
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Targeting therapeutic liabilities engendered by PIK3R1 mutations for cancer treatment
Pharmacogenomics, 2016Co-Authors: Lydia W T Cheung, Gordon B. MillsAbstract:The regulatory subunit of PI3K, p85α (encoded by PIK3R1), binds, stabilizes and inhibits the PI3K p110 catalytic subunit. Functional characterization of PIK3R1 mutations has identified not only hypomorphs with reduced inhibition of p110, but also hypomorphs and dominant negative mutants that disrupt a novel regulatory role of p85α on PTEN or neomorphs that activate unexpected signaling pathways. The diverse phenotypic spectrum of these PIK3R1 driver mutations underscores the need for different treatment strategies targeting tumors harboring these mutations. This article describes the functional consequences of the spectrum of PIK3R1 driver mutations and therapeutic liabilities they may engender.