Double
            <i>PIK3CA</i>
            mutations in cis increase oncogenicity and sensitivity to PI3Kα inhibitors

Vasan, Neil; Razavi, Pedram; Johnson, Jared L.; Shao, Hong; Shah, Hardik; Antoine, Alesia; Ladewig, Erik; Gorelick, Alexander N.; Lin, Ting‐Yu; Toska, Eneda; Xu, Guotai; Kazmi, Abiha; Chang, Matthew T.; Taylor, Barry S.; Dickler, Maura N.; Jhaveri, Komal; Chandarlapaty, Sarat; Rabadán, Raúl; Reznik, Ed; Smith, Melissa; Sebra, Robert; Schimmöller, Frauke; Wilson, Timothy R.; Friedman, Lori S.; Cantley, Lewis C.; Baselga, José

doi:10.1126/science.aaw9032

Cited by 228 publications

(270 citation statements)

References 74 publications

(52 reference statements)

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“…S3). This thought-provoking observation, although only hypothesis-generating at this point given the small sample size, does echo one recently observed with PI3K inhibitors, where patients with double mutations in the same allele of PIK3CA resulting in hyperactivation of PI3K signaling and increased oncogenicity had enhanced sensitivity to therapy targeting PI3K ( 11 ). In our analysis, the presence of an AKT1 mutation remained important, however, as patients with PI3K pathway activation in the absence of a coincident AKT1 mutation seemed to fare the same on an mTOR inhibitor as patients without any hit in the pathway.…”

Section: Genomic Comparisonsupporting

confidence: 74%

Characteristics and Outcome of AKT1E17K-Mutant Breast Cancer Defined through AACR Project GENIE, a Clinicogenomic Registry

et al. 2020

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AKT inhibitors have promising activity in AKT1 E17K-mutant estrogen receptor (ER)positive metastatic breast cancer, but the natural history of this rare genomic subtype remains unknown. Utilizing AACR Project GENIE, an international clinicogenomic data-sharing consortium, we conducted a comparative analysis of clinical outcomes of patients with matched AKT1 E17K-mutant (n = 153) and AKT1-wild-type (n = 302) metastatic breast cancer. AKT1-mutant cases had similar adjusted overall survival (OS) compared with AKT1-wild-type controls (median OS, 24.1 vs. 29.9, respectively; P = 0.98). AKT1-mutant cases enjoyed longer durations on mTOR inhibitor therapy, an observation previously unrecognized in pivotal clinical trials due to the rarity of this alteration. Other baseline clinicopathologic features, as well as durations on other classes of therapy, were broadly similar. In summary, we demonstrate the feasibility of using a novel and publicly accessible clincogenomic registry to defi ne outcomes in a rare genomically defi ned cancer subtype, an approach with broad applicability to precision oncology. SIGNIFICANCE: We delineate the natural history of a rare genomically distinct cancer, AKT1 E17Kmutant ER-positive breast cancer, using a publicly accessible registry of real-world patient data, thereby illustrating the potential to inform drug registration through synthetic control data.

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Section: Genomic Comparisonsupporting

confidence: 74%

Characteristics and Outcome of AKT1E17K-Mutant Breast Cancer Defined through AACR Project GENIE, a Clinicogenomic Registry

et al. 2020

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“…This demonstrates the utility of PIK3CA-centric stratification, yet a substantial proportion of patients with PIK3CA-mutant tumours did not benefit from the BYL719 and fulvestrant combination [22]. Although recent studies demonstrated that double PIK3CA mutations in cis confer greater sensitivity to PI3Kα inhibition, these studies focused on inhibition of proliferation/growth [7,8]. Such parameters do not strictly correlate with dedifferentiation or 'stemness' which are more strongly linked with metastasis and ultimately death.…”

Section: Discussionmentioning

confidence: 99%

“…We and others have recently shown that many PIK3CA-associated cancers harbour multiple independent mutations activating the PI3K pathway, including multiple PIK3CA mutations in cis or trans [3,[5][6][7][8]. We further reported that human induced pluripotent stem cells (iPSCs) with two endogenous alleles of the strongly activating cancer "hotspot" mutation PIK3CA H1047R exhibit pronounced phenotypic differences to isogenic cells heterozygous for the same PIK3CA variant [6].…”

Section: Introductionmentioning

confidence: 89%

Transcriptomically-inferred PI3K activity and stemness show a counterintuitive correlation withPIK3CAgenotype in breast cancer

Madsen

Rueda

Robin

et al. 2020

Preprint

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ABSTRACTThe development of reliable, prognostically informative molecular tests to direct targeted cancer therapy is a major challenge. In 2019, the PI3Kα inhibitor alpelisib was approved for the treatment of advanced breast cancer, in combination with the oestrogen receptor degrader fulvestrant, with some evidence for improved therapeutic response in patients classified as having tumours which were positive for mutation in PIK3CA, the gene encoding PI3Kα. Using human pluripotent stem cells, we recently demonstrated that the PIK3CAH1047R oncogenic hotspot variant shows marked PIK3CA allele dose-dependent activation of PI3K signalling and induction of self-sustained stemness. Together with recent discoveries of multi-copy and double-cis PIK3CA mutations in human cancers, this calls for a re-evaluation of the PIK3CA genotype-phenotype relationship and the current use of binary stratification by PIK3CA mutation status. Using computational analyses, we thus investigated the relationship between PIK3CA mutational status, PI3K activity/signalling strength and stemness. Stemness and PI3K activity scores were calculated using open-source methods and well-established transcriptional signatures. We report that a high PI3K pathway activity score, but not the presence of PIK3CA mutation per se, predicts increased breast cancer dedifferentiation and higher stemness, correlating with reduced overall survival. Our data (1) corroborate reports that the presence of a PIK3CA mutation per se does not predict high PI3K pathway activation or poor prognosis; (2) suggest that stratification of breast cancer for PI3K-based therapy might benefit from the use of a PI3K pathway activity score rather than binary PIK3CA mutation status alone; (3) suggest that combination of PI3K pathway inhibitors with differentiation-promoting treatments warrants evaluation in aggressive breast cancers with high PI3K activity and stemness scores.

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“…The PI3K signaling pathway is involved in the biological processes of cellular proliferation, apoptosis, survival, motility, and metastasis (40,41). Mutation in PIK3CA is present in most solid tumors (42) and is found in 12-15% of patients with breast cancers (43). A recent study has shown that mutation in PIK3CA corresponds to a poor prognosis in patients with hormone receptorpositive metastatic breast cancer but a good prognosis in patients with triple-negative breast cancer (44).…”

Section: Discussionmentioning

confidence: 99%

Integrative Bioinformatics Study Reveals Tangeretin Targets and Molecular Mechanisms Against Metastatic Breast Cancer

Hermawan

Putri

Hanif

et al. 2020

Preprint

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Background: Agents that target metastasis are important to improve treatment efficacy in patients with breast cancer. Tangeretin, a citrus flavonoid, exhibits antimetastatic effects on breast cancer cells, but its molecular mechanism remains unclear.Results: Tangeretin targets were retrieved from PubChem, whereas metastatic breast cancer regulatory genes were downloaded from PubMed. In total, 58 genes were identified as potential therapeutic target genes of tangeretin (PTs). Gene ontology analysis with Webgestalt showed that the PTs participate in the biological process of stimulus response, are the cellular components of the nucleus and the membrane, and play molecular roles in enzyme regulation. Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis revealed that the PTs regulate the PI3K/Akt pathway. Genetic alterations for each target gene were MTOR (3%), NOTCH1 (4%), TP53 (42%), MMP9 (4%), NFKB1 (3%), PIK3CA (32%), PTGS2 (15%), and RELA (5%). The Kaplan–Meier plot displayed that patients with low mRNA expression levels of MTOR, TP53, MMP9, NFKB1, PTGS2, and RELA and high expression of PIK3CA had a significantly better prognosis than their counterparts. Further validation of gene expression by using GEPIA revealed that the mRNA expression of MMP9 was significantly lower in breast cancer tissues than in normal tissues, whereas the mRNA expression of PTGS2 showed the opposite. Analysis with ONCOMINE demonstrated that the mRNA expression levels of MMP9 and NFKB1 were significantly higher in metastatic breast cancer cells than in normal tissues. The results of molecular docking analyses revealed the advantage of tangeretin as an inhibitor of PIK3CA, MMP9, PTGS2, and IKK.Conclusion: Tangeretin inhibits metastasis in breast cancer cells by targeting TP53, PTGS2, MMP9, and PIK3CA and regulating the PI3K/Akt signaling pathway. Further investigation is needed to validate the results of this study.

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Double PIK3CA mutations in cis increase oncogenicity and sensitivity to PI3Kα inhibitors

Cited by 228 publications

References 74 publications

Characteristics and Outcome of AKT1E17K-Mutant Breast Cancer Defined through AACR Project GENIE, a Clinicogenomic Registry

Characteristics and Outcome of AKT1E17K-Mutant Breast Cancer Defined through AACR Project GENIE, a Clinicogenomic Registry

Transcriptomically-inferred PI3K activity and stemness show a counterintuitive correlation withPIK3CAgenotype in breast cancer

Integrative Bioinformatics Study Reveals Tangeretin Targets and Molecular Mechanisms Against Metastatic Breast Cancer

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