Mutational Landscape of PI3K-AKT-mTOR Pathway in Breast Cancer: Implications for Targeted Therapeutics

Xiao, Weikai; Zhang, Guochun; Chen, Bin; Chen, Xiaoqing; Li, Wen; Lai, Jianguo; Li, Min; Líu, Hao; Liu, Jing; Han‐Zhang, Han; Lizaso, Analyn; Liao, Ning

doi:10.7150/jca.52993

Cited by 20 publications

(10 citation statements)

References 34 publications

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“…PIK3CA mutations were found in only 2 of 14 evaluated male BC cases that is lower than previously reported by our group in women with BC[ 19 , 20 ]. Piscuoglio et al [ 2 ] sequenced 241 genes in 59 male BC and found that most recurrent mutations affected the PIK3CA gene (20%).…”

Section: Discussioncontrasting

confidence: 73%

“…However, these rates would be lower than their female counterparts that have been detected in approximately 30%-40% of female BC[ 21 ]. In vitro and translational research in tumor samples from clinical trials found that PIK3CA mutations reduce sensitivity to anti-HER2 drugs[ 22 ] and endocrine modulation[ 19 , 20 ]. Additionally, a recent study demonstrates that Alpelisib, a drug targeting the PIK3CA pathway, has activity in breast cancer cases with presence of the mutation[ 12 ].…”

Section: Discussionmentioning

confidence: 99%

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A biomarker study in Peruvian males with breast cancer

Castañeda¹,

Castillo²,

Bernabe³

et al. 2021

WJCO

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BACKGROUND Breast cancer (BC) frequency in males is extremely low and tumor features vary from its female counterpart. Breast cancer clinical and pathological features differ by race in women. Tumor infiltrating lymphocyte (TIL) levels, mismatch repair (MMR) protein loss, androgen receptor (AR) expression, and PIK3CA gene mutations are predictive biomarkers of response to biological therapy in female BC. There is limited information about clinical and pathological features as well as predictive biomarkers in males of non-Caucasian races with BC. AIM To investigate clinicopathological features and biomarkers of BC tumors in males and their prognostic value in Peruvian population. METHODS This study looked at a single-institution series of 54 Peruvian males with invasive BC who were diagnosed from Jan 2004 to June 2018. Standard pathological features, TIL levels, MMR proteins, AR immunohistochemistry staining, and PIK3CA gene mutations were prospectively evaluated in cases with available paraffin material. Percentage of AR and estrogen receptor (ER) positive cells was additionally calculated by software after slide scanning. Statistical analyses included association tests, intraclass correlation test and Kaplan Meier overall survival curves. RESULTS The median age was 63 years and most cases were ER-positive (85.7%), HER2 negative (87.2%), Luminal-A phenotype (60%) and clinical stage II (41.5%) among our male breast tumors. Median TIL was 10% and higher levels tended to be associated with Luminal-B phenotype and higher grade. AR-positive was found in 85.3% and was correlated with ER (intraclass index of 0.835, P < 0.001). Loss of MMR proteins was found in 15.4% and PIK3CA mutation (H1047R) in 14.3% (belonged to the Luminal-A phenotype). Loss of MMR proteins was associated with AR-negative ( P = 0.018) but not with ER ( P = 0.43) or TIL ( P = 0.84). Early stages ( P < 0.001) and lower grade ( P = 0.006) were associated with longer overall survival. ER status, phenotype, AR status, TIL level, MMR protein loss nor PIK3CA mutation was not associated with survival ( P > 0.05). CONCLUSION Male BC is usually ER and AR positive, and Luminal-A. MMR loss and PIK3CA mutations are infrequent. Stage and grade predicted overall survival in our South American country population.

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Section: Discussioncontrasting

confidence: 73%

Section: Discussionmentioning

confidence: 99%

A biomarker study in Peruvian males with breast cancer

Castañeda¹,

Castillo²,

Bernabe³

et al. 2021

WJCO

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“…The PI3K/AKT/mTOR signalling pathway is particularly relevant due to its central role in cell growth, proliferation, survival, motility, metabolism, and immune response [ 103 , 104 ]. Alterations and hyperactivation of the PI3K/AKT/mTOR pathway are observed in many cancers, with estimations that aberrations are present in 60–70% of breast cancers [ 103 , 105 , 106 ]. The observation that somatic alterations in receptor tyrosine kinase (RTK; e.g., HER, FGFR receptors), RAS [e.g., neurofibromatosis type 1 (NF1)] and PI3K/AKT/mTOR (e.g., AKT1) pathways occur at higher frequency in endocrine resistant/metastatic disease compared with primary disease highlight the importance of these growth processes in endocrine resistance [ 102 ].…”

Section: Molecular Characterization Of In Vitro Mo...mentioning

confidence: 99%

In vitro breast cancer models for studying mechanisms of resistance to endocrine therapy

Cheng

Leung

Singleton

2022

Exploration of Targeted Anti-Tumor Therapy

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The development of endocrine resistance is a common reason for the failure of endocrine therapies in hormone receptor-positive breast cancer. This review provides an overview of the different types of in vitro models that have been developed as tools for studying endocrine resistance. In vitro models include cell lines that have been rendered endocrine-resistant by ex vivo treatment; cell lines with de novo resistance mechanisms, including genetic alterations; three-dimensional (3D) spheroid, co-culture, and mammosphere techniques; and patient-derived organoid models. In each case, the key discoveries, different analysis strategies that are suitable, and strengths and weaknesses are discussed. Certain recently developed methodologies that can be used to further characterize the biological changes involved in endocrine resistance are then emphasized, along with a commentary on the types of research outcomes that using these techniques can support. Finally, a discussion anticipates how these recent developments will shape future trends in the field. We hope this overview will serve as a useful resource for investigators that are interested in understanding and testing hypotheses related to mechanisms of endocrine therapy resistance.

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“…Strategies to overcome tumor hypoxia adaptation include disrupting HIF signaling, suppressing TME acidosis, mediating metabolism and targeting hypoxic tumor cells pathways [ 20 , 21 ]. As a key point to tumor anabolism, mTOR is mainly activated by phosphatidylinositol-3 kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR) signal [ 22 ], which also regulates HIF-1α translation [ 23 , 24 ]. Meanwhile, mTOR is a therapeutic target for tumors due to the function in promoting the synthesis of amino acids, glucose and other substances required for cancer cell growth, enabling tumors metastasis and anti-apoptosis [ 25 ].…”

Section: Introductionmentioning

confidence: 99%

Carbonic anhydrase IX-targeted H-APBC nanosystem combined with phototherapy facilitates the efficacy of PI3K/mTOR inhibitor and resists HIF-1α-dependent tumor hypoxia adaptation

Liu

Feng

et al. 2022

J Nanobiotechnol

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Background Non-redundant properties such as hypoxia and acidosis promote tumor metabolic adaptation and limit anti-cancer therapies. The key to the adaptation of tumor cells to hypoxia is the transcriptional and stable expression of hypoxia-inducible factor-1 alpha (HIF-1α). The phosphorylation-activated tumorigenic signal PI3K/AKT/mTOR advances the production of downstream HIF-1α to adapt to tumor hypoxia. Studies have elucidated that acid favors inhibition of mTOR signal. Nonetheless, carbonic anhydrase IX (CAIX), overexpressed on membranes of hypoxia tumor cells with pH-regulatory effects, attenuates intracellular acidity, which is unfavorable for mTOR inhibition. Herein, a drug delivery nanoplatform equipped with dual PI3K/mTOR inhibitor Dactolisib (NVP-BEZ235, BEZ235) and CAIX inhibitor 4‐(2‐aminoethyl) benzene sulfonamide (ABS) was designed to mitigate hypoxic adaptation and improve breast cancer treatment. Results ABS and PEG-NH2 were successfully modified on the surface of hollow polydopamine (HPDA), while BEZ235 and Chlorin e6 (Ce6) were effectively loaded with the interior of HPDA to form HPDA-ABS/PEG-BEZ235/Ce6 (H-APBC) nanoparticles. The release of BEZ235 from H-APBC in acid microenvironment could mitigate PI3K/mTOR signal and resist HIF-1α-dependent tumor hypoxia adaptation. More importantly, ABS modified on the surface of H-APBC could augment intracellular acids and enhances the mTOR inhibition. The nanoplatform combined with phototherapy inhibited orthotopic breast cancer growth while reducing spontaneous lung metastasis, angiogenesis, based on altering the microenvironment adapted to hypoxia and extracellular acidosis. Conclusion Taken together, compared with free BEZ235 and ABS, the nanoplatform exhibited remarkable anti-tumor efficiency, reduced hypoxia adaptation, mitigated off-tumor toxicity of BEZ235 and solved the limited bioavailability of BEZ235 caused by weak solubility. Graphical Abstract

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Mutational Landscape of PI3K-AKT-mTOR Pathway in Breast Cancer: Implications for Targeted Therapeutics

Cited by 20 publications

References 34 publications

A biomarker study in Peruvian males with breast cancer

A biomarker study in Peruvian males with breast cancer

In vitro breast cancer models for studying mechanisms of resistance to endocrine therapy

Carbonic anhydrase IX-targeted H-APBC nanosystem combined with phototherapy facilitates the efficacy of PI3K/mTOR inhibitor and resists HIF-1α-dependent tumor hypoxia adaptation

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