Targeting Therapeutic Liabilities Engendered by
            <i>PIK3R1</i>
            Mutations for Cancer Treatment

Cheung, Lydia W.T.; Mills, Gordon B.

doi:10.2217/pgs.15.174

Cited by 43 publications

(37 citation statements)

References 94 publications

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“…Finally, the nearby Cluster 11 (which is discussed in more detail later) contains the wild-type form of CDC42 as well as TRAF2, a canonical NF-κB activator; these two are known to interact and share functions in actin remodeling (Marivin et al, 2014). We also note that anti-correlating genes to these clusters (generally in Clusters 13 and 21) are consistent with existing knowledge, including (a) AKT family member AKT1S1 (a Proline rich AKT substrate, PRAS40 (Kovacina et al, 2003; Wiza et al, 2014), Supplementary file 2 [PDF 7A, panels b1 and c1]) (b) CDK2 (a known target of Akt [Maddika et al, 2008]), (c) PIK3R1 and PTEN in Cluster 21, described previously, which have known interactions with AKT (Cheung and Mills, 2016; Hemmings and Restuccia, 2015). Thus, all of these connections have previously been identified.…”

Section: Resultssupporting

confidence: 87%

Systematic morphological profiling of human gene and allele function via Cell Painting

Rohban

Singh

et al. 2017

eLife

157

152

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We hypothesized that human genes and disease-associated alleles might be systematically functionally annotated using morphological profiling of cDNA constructs, via a microscopy-based Cell Painting assay. Indeed, 50% of the 220 tested genes yielded detectable morphological profiles, which grouped into biologically meaningful gene clusters consistent with known functional annotation (e.g., the RAS-RAF-MEK-ERK cascade). We used novel subpopulation-based visualization methods to interpret the morphological changes for specific clusters. This unbiased morphologic map of gene function revealed TRAF2/c-REL negative regulation of YAP1/WWTR1-responsive pathways. We confirmed this discovery of functional connectivity between the NF-κB pathway and Hippo pathway effectors at the transcriptional level, thereby expanding knowledge of these two signaling pathways that critically regulate tumor initiation and progression. We make the images and raw data publicly available, providing an initial morphological map of major biological pathways for future study.DOI: http://dx.doi.org/10.7554/eLife.24060.001

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Section: Resultssupporting

confidence: 87%

Systematic morphological profiling of human gene and allele function via Cell Painting

Rohban

Singh

et al. 2017

eLife

157

152

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“…Consistent with pre-existing data [31,32], aberrations of the PI3K pathway were the most frequent targetable genetic alterations. PIK3CA mutation was detected in 11%, followed by alterations of the core member PIK3R1 present in 7% of patients and discussed as biomarker of responsiveness if targeting the PI3K pathway [33]. KRAS was mutated in 14%, and associated with lower grade and mucinous subtype, as already previously published [31,34].…”

Section: Discussionsupporting

confidence: 58%

Precision Medicine Tumor Boards: Clinical Applicability of Personalized Treatment Concepts in Ovarian Cancer

Aust

Schwameis

Gagic

et al. 2020

Cancers

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Background: Treating cancer according to its molecular alterations (i.e., targeted treatment, TT) is the goal of precision medicine tumor boards (PTBs). Their clinical applicability has been evaluated for ovarian cancer patients in this analysis. Methods: All consecutive ovarian cancer patients discussed in a PTB at the Medical University of Vienna, Austria, from April 2015 to April 2019 were included (n = 44). Results: In 38/44 (86%) cases, at least one mutation, deletion or amplification was detected. The most frequently altered genes were p53 (64%), PI3K pathway (18%), KRAS (14%), BRCA1 (11%) and BRCA2 (2%). In 31 patients (70%) a TT was recommended. A total of 12/31 patients (39%) received the recommended therapy. Median time from indication for PTB to TT start was 65 days (15–216). Median time to treatment failure was 2.7 months (0.2–13.2). Clinical benefit rate (CBR) was 42%. Reasons for treatment discontinuation were disease progression (42%), poor performance status (PS > 2; 25%), death (17%) or treatment related side effects (8%). In 61% the TT was not administered—mainly due to PS > 2. Conclusion: Even though a TT recommendation can be derived frequently, clinical applicability remains limited due to poor patients’ general condition after exploitation of standard treatment. However, we observed antitumor activity in a substantial number of heavily pretreated patients.

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“…Indeed, HIF1a has been well studied in cancer progression and is implicated in the malignancy phenotype of LSCC [37–38]. Phosphoinositide-3-kinase regulatory subunit 1(PIK3R1) binds, stabilizes and inhibits the PI3K p110 catalytic subunit [39]. Previous studies show that PIK3R1 suppresses tumor cell invasion and migration by reducing PI3K/AKT signaling [40].…”

Section: Discussionmentioning

confidence: 99%

Integrated Analysis of Long Noncoding RNA and mRNA Expression Profile in Advanced Laryngeal Squamous Cell Carcinoma

Wang

Lian

et al. 2016

PLoS ONE

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Long non-coding RNA (lncRNA) plays an important role in tumorigenesis. However, the expression pattern and function of lncRNAs in laryngeal squamous cell carcinoma (LSCC) are still unclear. To investigate the aberrantly expressed lncRNAs and mRNAs in advanced LSCC, we screened lncRNA and mRNA expression profiles in 9 pairs of primary Stage IVA LSCC tissues and adjacent non-neoplastic tissues by lncRNA and mRNA integrated microarrays. Gene Ontology and pathway analysis were performed to find out the significant function and pathway of the differentially expressed mRNAs, gene-gene functional interaction network and ceRNA network were constructed to select core mRNAs, and lncRNA-mRNA expression correlation network was built to identify the interactions between lncRNA and mRNA. qRT-PCR was performed to further validate the expressions of selected lncRNAs and mRNAs in advanced LSCC. We found 1459 differentially expressed lncRNAs and 2381 differentially expressed mRNAs, including 846 up-regulated lncRNAs and 613 down-regulated lncRNAs, 1542 up-regulated mRNAs and 839 down-regulated mRNAs. The mRNAs ITGB1, HIF1A, and DDIT4 were selected as core mRNAs, which are mainly involved in biological processes, such as matrix organization, cell cycle, adhesion, and metabolic pathway. LncRNA-mRNA expression correlation network showed LncRNA NR_027340, MIR31HG were positively correlated with ITGB1, HIF1A respectively. LncRNA SOX2-OT was negatively correlated with DDIT4. qRT-PCR further validated the expression of these lncRNAs and mRNAs. The work provides convincing evidence that the identified lncRNAs and mRNAs are potential biomarkers in advanced LSCC for further future studies.

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Targeting Therapeutic Liabilities Engendered by PIK3R1 Mutations for Cancer Treatment

Cited by 43 publications

References 94 publications

Systematic morphological profiling of human gene and allele function via Cell Painting

Systematic morphological profiling of human gene and allele function via Cell Painting

Precision Medicine Tumor Boards: Clinical Applicability of Personalized Treatment Concepts in Ovarian Cancer

Integrated Analysis of Long Noncoding RNA and mRNA Expression Profile in Advanced Laryngeal Squamous Cell Carcinoma

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