Novel Therapies and Strategies to Overcome Resistance to Anti-HER2-Targeted Drugs

Gámez-Chiachio, Manuel; Sarrió, David; Moreno‐Bueno, Gema

doi:10.3390/cancers14184543

Cited by 15 publications

(13 citation statements)

References 214 publications

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“…EGFR/HER2 signaling pathway has a crucial role in acquired endocrine resistance, and the exact mechanisms that underlie merit further investigation. For example, both EGFR/HER2 apart from their ability to activate oncogenic signaling can also regulate autophagy, which is involved in the development of hormone-therapy resistance ( 60 – 62 ). Both EGFR/HER2 signaling and autophagy cooperate during the development of endocrine resistance.…”

Section: Discussionmentioning

confidence: 99%

Resistance to hormone therapy in breast cancer cells promotes autophagy and EGFR signaling pathway

Siatis

Giannopoulou

Manou³

et al. 2023

American Journal of Physiology-Cell Physiology

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Breast cancer is the leading cause of cancer deaths for women worldwide. Endocrine therapies represent the cornerstone for hormone-dependent breast cancer treatment. However, in many cases, endocrine resistance is induced with poor prognosis for patients. In the current study, we have developed MCF-7 cell lines resistant to Fulvestrant (MCF-7Fulv) and Tamoxifen (MCF-7Tam) aiming at investigating mechanisms underlying resistance. Both resistant cell lines exerted lower proliferation capacity in 2D cultures but retain ERα expression and proliferate independent of the presence of estrogens. The established cell lines tend to be more aggressive exhibiting advanced capacity to form colonies, increased expression of epidermal growth factor receptor (EGFR), human epidermal growth factor receptor 2 (HER2), and heterodimerization of ERBB family receptors and activation of EGFR downstream pathways like MEK/ERK1/2 and PI3K/AKT. Tyrosine kinase inhibitors tested against resistant MCF-7Fulv and MCF-7Tam cells, showed moderate efficacy to inhibit cell proliferation except for lapatinib, which concomitantly inhibits both EGFR and HER2 receptors, and strongly reduced cell proliferation. Furthermore, increased autophagy was observed in resistant MCF-7Fulv and MCF-7Tam cells as shown by the presence of autophagosomes and increased Beclin-1 levels. The increased autophagy in resistant cells is not associated with increased apoptosis suggesting a cytoprotective role for autophagy that may favor cells' survival and aggressiveness. Thus, by exploiting those underlying mechanisms, new targets could be established to overcome endocrine resistance.

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Section: Discussionmentioning

confidence: 99%

Resistance to hormone therapy in breast cancer cells promotes autophagy and EGFR signaling pathway

Siatis

Giannopoulou

Manou³

et al. 2023

American Journal of Physiology-Cell Physiology

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“…These cancer cells exhibit not only strong proliferative abilities but also resistance to certain chemotherapy drugs. Even after undergoing surgical treatment, there remains a high likelihood of cancer cell recurrence and metastasis, resulting in limited long-term survival for patients ( Gámez-Chiachio et al, 2022 ). Therefore, HER2 plays a pivotal role in cancer screening and targeted treatment.…”

Section: Surface Antigen Of Tumor Cells: Her2mentioning

confidence: 99%

Antibody-drug conjugates targeting HER2 for the treatment of urothelial carcinoma: potential therapies for HER2-positive urothelial carcinoma

Shih,

Lin,

Luo

et al. 2024

Front. Pharmacol.

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Urothelial carcinoma (UC) is a common cancer characterized by high morbidity and mortality rates. Despite advancements in treatment, challenges such as recurrence and low response rates persist. Antibody-drug conjugates (ADCs) have emerged as a promising therapeutic approach for various cancers, although their application in UC is currently limited. This review focuses on recent research regarding ADCs designed to treat UC by targeting human epidermal growth factor receptor 2 (HER2), a surface antigen expressed on tumor cells. ADCs comprise three main components: an antibody, a linker, and a cytotoxic payload. The antibody selectively binds to tumor cell surface antigens, facilitating targeted delivery of the cytotoxic drug, while linkers play a crucial role in ensuring stability and controlled release of the payload. Cleavable linkers release the drug within tumor cells, while non-cleavable linkers ensure stability during circulation. The cytotoxic payload exerts its antitumor effect by disrupting cellular pathways. HER2 is commonly overexpressed in UCs, making it a potential therapeutic target. Several ADCs targeting HER2 have been approved for cancer treatment, but their use in UC is still being tested. Numerous HER2 ADCs have demonstrated significant growth inhibition and induction of apoptosis in translational models of HER2-overexpressing bladder cancer. Ongoing clinical trials are assessing the efficacy and safety of ADCs targeting HER2 in UC, with the aim of determining tumor response and the potential of ADCs as a treatment option for UC patients. The development of effective therapies with improved response rates and long-term effectiveness is crucial for advanced and metastatic UC. ADCs targeting HER2 show promise in this regard and merit further investigation for UC treatment.

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“…Over-activation of the PI3K/AKT/mTOR pathway is thought to be among the dominating causes of carcinogenicity, which is linked to various resistance mechanisms to anti-HER2 therapy ( 69 ). Pre-clinical evidence has shown that the PI3K/Akt/mTOR pathway contributes to HER2-directed therapy resistance, making it a new target for the treatment of HER2-resistant disease in clinical development ( 70 ).…”

Section: Cdk4/6 Inhibitors Overcome Resistance To Targeted Therapy In...mentioning

confidence: 99%

Clinical considerations of CDK4/6 inhibitors in HER2 positive breast cancer

Zhang,

Zhou,

Zou

et al. 2024

Front. Oncol.

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Deregulation of cell cycles can result in a variety of cancers, including breast cancer (BC). In fact, abnormal regulation of cell cycle pathways is often observed in breast cancer, leading to malignant cell proliferation. CDK4/6 inhibitors (CDK4/6i) can block the G1 cell cycle through the cyclin D-cyclin dependent kinase 4/6-inhibitor of CDK4-retinoblastoma (cyclinD-CDK4/6-INK4-RB) pathway, thus blocking the proliferation of invasive cells, showing great therapeutic potential to inhibit the spread of BC. So far, three FDA-approved drugs have been shown to be effective in the management of advanced hormone receptor positive (HR+) BC: palbociclib, abemaciclib, and ribociclib. The combination strategy of CDK4/6i and endocrine therapy (ET) has become the standard therapeutic regimen and is increasingly applied to advanced BC patients. The present study aims to clarify whether CDK4/6i can also achieve a certain therapeutic effect on Human epidermal growth factor receptor 2 positive (HER2+) BC. Studies of CDK4/6i are not limited to patients with estrogen receptor positive/human epidermal growth factor receptor 2 negative (ER+/HER2-) advanced BC, but have also expanded to other types of BC. Several pre-clinical and clinical trials have demonstrated the potential of CDK4/6i in treating HER2+ BC. Therefore, this review summarizes the current knowledge and recent findings on the use of CDK4/6i in this type of BC, and provides ideas for the discovery of new treatment modalities.

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Novel Therapies and Strategies to Overcome Resistance to Anti-HER2-Targeted Drugs

Cited by 15 publications

References 214 publications

Resistance to hormone therapy in breast cancer cells promotes autophagy and EGFR signaling pathway

Resistance to hormone therapy in breast cancer cells promotes autophagy and EGFR signaling pathway

Antibody-drug conjugates targeting HER2 for the treatment of urothelial carcinoma: potential therapies for HER2-positive urothelial carcinoma

Clinical considerations of CDK4/6 inhibitors in HER2 positive breast cancer

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