HER family in cancer progression: From discovery to 2020 and beyond

Kumar, Rakesh; George, B; Campbell, Margaret L.; Verma, Nandini; Paul, Aswathy Mary; Melo-Alvim, Cecília; Ribeiro, Leonor; Pillai, M. Radhakrishna; Costa, Luís; Moasser, Mark M.

doi:10.1016/bs.acr.2020.04.001

Cited by 40 publications

(40 citation statements)

References 256 publications

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“…Cell surface receptor tyrosine kinases (RTKs) represent the first interface for transduction of the signal from extracellular polypeptide growth factors. In cancer cells, central to RTK functionality is the ability of specific ligands to bind to its receptors and stimulate its tyrosine kinase activity, thus engaging a multitude of signaling cascades [1][2][3]. Among RTK family members, HER family members act as a prototype largely because of their historical perspective and widespread hyperactivation in human cancers as well as their ability to coordinate many cellular processes that cumulatively lead to oncogenesis [1][2][3].…”

Section: The Her Familymentioning

confidence: 99%

“…This was followed by the discovery of erbB/HER3 as a homolog of EGFR using the EGFR probe in a low-stringency hybridization-based screening [23,24]. Like EGFR and HER2, HER3 is also widely overexpressed in human cancer [3]. The last HER family member, the HER4, was cloned from a complementary DNA (cDNA) library, prepared from breast cancer cells, and screened with a set of degenerated primers complementary to the conserved EGFR catalytic region [25].…”

Section: The Her Familymentioning

confidence: 99%

“…Binding of ligands to the HER triggers intramolecular conformational changes in the receptor, thus facilitating dimerization of HER monomers, phosphorylation of tyrosine residues in the carboxyl terminal of the receptor, and engagement of signaling cascades (Fig. 1b) [3]. Among HER family members, HER2 lacks a specific ligand, whereas HER3 binds to its ligands with a high affinity but does not have autophosphorylation capacity.…”

Section: The Her Familymentioning

confidence: 99%

“…Among HER family members, HER2 lacks a specific ligand, whereas HER3 binds to its ligands with a high affinity but does not have autophosphorylation capacity. Although HER3 lacks catalytic activity, it is actively involved in allosteric regulation of interacting HERs (discussed below) and in scaffolding activity and transcriptional functions [3]. These structural features make EGFR, HER2, and HER3 targets of HER ligands for stimulating combinational heterodimerization with other HER members, leading to signaling in a context-dependent manner [1][2][3].…”

Section: The Her Familymentioning

confidence: 99%

“…Dysregulation of cell surface receptors that transduce extracellular signals as well as cytoskeleton remodeling of cancer cells are two prominent interconnected aspects of oncogenesis. We here therefore briefly summarize the discoveries and significant advances in the areas of human epidermal growth factor receptors (HERs) [1][2][3][4][5][6][7] and p21-activated kinases (PAKs, a class of serine/threonine kinases [8][9][10][11][12][13] as examples of coordinated regulation of molecules in cancer progression. In addition, we discuss how epidermal growth factor receptor (EGFR)-and HER2-driven studies initially discovered the role of the PAK pathway in conferring invasiveness to breast cancer cells, thereby PAKs making an inroad to cancer biology and revealing the significance of PAKs in cancer progression and metastasis.…”

Section: Introductionmentioning

confidence: 99%

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Coordinated dysregulation of cancer progression by the HER family and p21-activated kinases

Kumar

Paul

Revikumar

et al. 2020

Cancer Metastasis Rev

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Most epithelial cancer types are polygenic in nature and are driven by coordinated dysregulation of multiple regulatory pathways, genes, and protein modifications. The process of coordinated regulation of cancer promoting pathways in response to extrinsic and intrinsic signals facilitates the dysregulation of several pathways with complementary functions, contributing to the hallmarks of cancer. Dysregulation and hyperactivation of cell surface human epidermal growth factor receptors (HERs) and cytoskeleton remodeling by p21-activated kinases (PAKs) are two prominent interconnected aspects of oncogenesis. We briefly discuss the discoveries and significant advances in the area of coordinated regulation of HERs and PAKs in the development and progression of breast and other epithelial cancers. We also discuss how initial studies involving heregulin signaling via HER3-HER2 axis and HER2-overexpressing breast cancer cells not only discovered a mechanistic role of PAK1 in breast cancer pathobiology but also acted as a bridge in generating a broader cancer research interest in other PAK family members and cancer types and catalyzed establishing the role of PAKs in human cancer, at-large. In addition, growth factor stimulation of the PAK pathway also helped to recognize new facets of PAKs, connecting the PAK pathway to oncogenesis, nuclear signaling, gene expression, mitotic progression, DNA damage response, among other phenotypic responses, and shaped the field of PAK cancer research. Finally, we recount some of the current limitations of HER-and PAK-directed therapeutics in counteracting acquired therapeutic resistance and discuss how cancer's as a polygenic disease may be best targeted with a polygenic approach.

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Section: The Her Familymentioning

confidence: 99%

Section: The Her Familymentioning

confidence: 99%

Section: The Her Familymentioning

confidence: 99%

Section: The Her Familymentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Coordinated dysregulation of cancer progression by the HER family and p21-activated kinases

Kumar

Paul

Revikumar

et al. 2020

Cancer Metastasis Rev

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3D‐Cell Spotter Cooperated High‐Throughput Screening (HTS) for Estimating Targeted Drugs in Breast Cancer Cells

Lee

Hwang

Lee

2022

Advanced Therapeutics

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A 3D-cell spotter is developed to maximize the efficiency of 3D cell-based high-throughput screening (3D-HTS). The performance of 3D-HTS is verified through heatmap analysis for distinguishing responses to targeted drugs according to the expression of HER2 in breast cancer cells. Under 2D culture, the expression of cell proliferation receptors is lost as cells adhere to the bottom of the plate. To address this issue, alginate is applied as an extracellular matrix to the 3D cell culture to maintain the expression of tumor-associated proteins. In general, higher drug resistance is observed with 3D-HTS. However, increased drug resistance does not necessarily mean decreased analytical sensitivity to drug responsiveness. In particular, with 3D-HTS, EGFR-targeted drug reactivity to HER2-positive and -negative cell lines are distinguished by a higher positive/negative (P/N) score, and more combinations of strong correlations between EGFR-targeted drugs are observed. After confirming the reactivity of 65 drugs using previous analysis results with heatmap analysis, two new non-EGFR-targeted drugs with excellent efficacy against breast cancer cells are identified. To verify this, high-content imaging analysis is conducted to assess their ability to inhibit phospho-EGFR activity. Therefore, the 3D-HTS-based heatmap analysis method is useful for analyzing the efficacy of targeted drugs against breast cancer cells.

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Overcoming Breast Cancer Resistance to Targeted, Chemo-, and Immuno Therapy: Mechanisms and Strategies to Overcome Resistance and Facilitate Drug Development

Hermawan,

Ucche,

Ibadurrahman

et al. 2024

Interdisciplinary Cancer Research

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HER family in cancer progression: From discovery to 2020 and beyond

Cited by 40 publications

References 256 publications

Coordinated dysregulation of cancer progression by the HER family and p21-activated kinases

Coordinated dysregulation of cancer progression by the HER family and p21-activated kinases

3D‐Cell Spotter Cooperated High‐Throughput Screening (HTS) for Estimating Targeted Drugs in Breast Cancer Cells

Overcoming Breast Cancer Resistance to Targeted, Chemo-, and Immuno Therapy: Mechanisms and Strategies to Overcome Resistance and Facilitate Drug Development

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