PI3K oncogenic mutations mediate resistance to afatinib in HER2/neu overexpressing gynecological cancers

Bonazzoli, Elena; Cocco, Emiliano; Lopez, Salvatore; Bellone, Stefania; Zammataro, Luca; Bianchi, Anna; Manzano, Aránzazu; Yadav, Ghanshyam; Manara, Paola; Perrone, Emanuele; Haines, Kaitlin; Espinal, Mariana; Dugan, Katherine; Menderes, Gulden; Altwerger, Gary; Han, Chanhee; Zeybek, Burak; Litkouhi, Babak; Ratner, Elena; Silasi, Dan‐Arin; Huang, Gloria S.; Azodi, Masoud; Schwartz, Peter E.; Santin, Alessandro D.

doi:10.1016/j.ygyno.2019.01.002

Cited by 15 publications

(8 citation statements)

References 40 publications

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“…Another study described the progression of disease on trastuzumab with paclitaxel in three women with HER2+ recurrent high-risk histology tumors including two serous and one endometrioid [86]. In vitro experiments in cells that overexpress ERBB2 showed that oncogenic mutations in PI3K resulted in resistance to afatinib, a tyrosine kinase inhibitor that inhibits ErbB signaling [87]. A randomized trial of systemic chemotherapy (carboplatin and paclitaxel) with trastuzumab in serous carcinomas increased median progression-free survival from 8.0 months to 12.6 months.…”

Section: Treatmentmentioning

confidence: 99%

Unique Molecular Features in High-Risk Histology Endometrial Cancers

Pandita

Wang

Jones

et al. 2019

Cancers

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Endometrial cancer is the most common gynecologic malignancy in the United States and the sixth most common cancer in women worldwide. Fortunately, most women who develop endometrial cancer have low-grade early-stage endometrioid carcinomas, and simple hysterectomy is curative. Unfortunately, 15% of women with endometrial cancer will develop high-risk histologic tumors including uterine carcinosarcoma or high-grade endometrioid, clear cell, or serous carcinomas. These high-risk histologic tumors account for more than 50% of deaths from this disease. In this review, we will highlight the biologic differences between low- and high-risk carcinomas with a focus on the cell of origin, early precursor lesions including atrophic and proliferative endometrium, and the potential role of stem cells. We will discuss treatment, including standard of care therapy, hormonal therapy, and precision medicine-based or targeted molecular therapies. We will also discuss the impact and need for model systems. The molecular underpinnings behind this high death to incidence ratio are important to understand and improve outcomes.

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Section: Treatmentmentioning

confidence: 99%

Unique Molecular Features in High-Risk Histology Endometrial Cancers

Pandita

Wang

Jones

et al. 2019

Cancers

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“…As AKT is directly phosphorylated by PIK3CA ( 41 ) and mTOR is a known downstream target of the ERBB2-PIK3CA-AKT axis ( 42 ), the expression levels of AKT phosphorylation (p-AKT/AKT) and mTOR phosphorylation (p-mTOR/mTOR) were assessed as indicators of PIK3CA activity. siERBB2 cells expressed significantly lower AKT and mTOR phosphorylation levels compared with siCtrl cells, while ERBB2 vec cells expressed significantly higher AKT and mTOR phosphorylation levels compared with Ctrl vec cells ( Fig.…”

Section: Resultsmentioning

confidence: 99%

Erb‑B2 Receptor Tyrosine Kinase 2 is negatively regulated by the p53‑responsive microRNA‑3184‑5p in cervical cancer cells

Liu

Zhang

et al. 2020

Oncol Rep

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The oncogenic role of Erb-B2 Receptor Tyrosine Kinase 2 (ERBB2) has been identified in several types of cancer, but less is known on its function and mechanism of action in cervical cancer cells. The present study employed a multipronged approach to investigate the role of ERBB2 in cervical cancer. ERBB2 and microRNA (miR)-3184-5p expression was assessed in patient-derived cervical cancer biopsy tissues, revealing that higher levels of ERBB2 and lower levels of miR-3184-5p were associated with clinicopathological indicators of cervical cancer progression. Furthermore, ERBB2 stimulated proliferation, migration and sphere-formation of cervical cancer cells in vitro. This effect was mediated by enhanced phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit α activity. Additionally, it was revealed that miR-3184-5p directly suppressed ERBB2 in cervical cancer cells. The p53 activator Mithramycin A stimulated p53 and miR-3184-5p expression, thereby lowering the levels of ERBB2 and attenuating proliferation, migration and sphere-formation of cervical cancer cells. In conclusion, the findings of the present study suggested ERBB2 as an oncogenic protein that may promote invasiveness in cervical cancer cells. Treatment of cervical cancer cells with the p53 activator Mithramycin A restored the levels of the endogenous ERBB2 inhibitor miR-3184-5p and may represent a novel treatment strategy for cervical cancer.

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“…The combination prevented resistance in preclinical USC models, and led to substantial cancer regression in large xenografts, previously resistant to single-agent PIK3CA or pan-Her inhibition. These preclinical results suggest that combination regimens using highly targeted drugs may be of great benefit while synergistic combinations could induce more durable clinical responses in USC [ 56 , 57 , 58 , 59 ].…”

Section: Immunotherapy and Tumor-draining Lymph Nodesmentioning

confidence: 99%

The Prognostic Role and Significance of Dll4 and Toll-like Receptors in Cancer Development

Fasoulakis

Koutras

Ntounis

et al. 2022

Cancers

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The Notch signaling pathway regulates the development of embryonic and tissue homeostasis of various types of cells. It also controls cell proliferation, variation, fate and cell death because it emits short-range messages to nearby cells. The pathway plays an important role in the pathophysiology of various malignancies, controlling cancer creation. It also limits cancer development by adjusting preserved angiogenesis and cellular programs. One of the Notch signaling ligands (in mammals) is Delta-like ligand 4 (Dll4), which plays a significant role in the overall malignancies’ advancement. Particularly, sequencing Notch gene mutations, including those of Dll4, have been detected in many types of cancers portraying information on the growth of particular gynecological types of tumors. The current research article examines the background theory that implies the ability of Dll4 in the development of endometrial and other cancer types, and the probable therapeutic results of Dll4 inhibition.

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PI3K oncogenic mutations mediate resistance to afatinib in HER2/neu overexpressing gynecological cancers

Cited by 15 publications

References 40 publications

Unique Molecular Features in High-Risk Histology Endometrial Cancers

Unique Molecular Features in High-Risk Histology Endometrial Cancers

Erb‑B2 Receptor Tyrosine Kinase 2 is negatively regulated by the p53‑responsive microRNA‑3184‑5p in cervical cancer cells

The Prognostic Role and Significance of Dll4 and Toll-like Receptors in Cancer Development

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