Hot Keywords
Drug Resistance Mechanisms Epigenetic Resistance in Cancer Therapy Biomarkers Pharmacogenetics of Cancer Liquid Biopsy Targeted Cancer Therapy Non-coding RNAs Kinase Inhibitors ABC Transporters

Topic: Molecular Mechanisms of Targeted Therapy Resistance in Breast Cancers

A special issue of Cancer Drug Resistance

ISSN 2578-532X (Online)

Submission deadline: 28 Feb 2022

Guest Editor(s)

  • Dr. Mark Pegram
    Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA.

    Website | E-mail

Special Issue Introduction

According to the World Health Organization (WHO), cancer is the first or second leading cause of death under 70 years in 112 of 183 countries, and in a further 23 countries, it ranks third or fourth[1]. In 2020, breast cancer was the most commonly diagnosed cancer in women, with 2,261,419 breast cancer cases diagnosed worldwide, and was the leading cause of cancer mortality in women -- 684,996 deaths[2]. These are prominent improvements in early detection and significant improvements in systemic adjuvant (and neoadjuvant) therapeutic approaches, including endocrine therapy for hormone receptor (HR) positive breast cancers (about 75% of all breast cancers), chemotherapeutic approaches, as well as molecularly-targeted therapeutics, particularly those targeting human epidermal growth factor receptor-2 (HER2) – HER2+ breast cancer accounting for about 15%-20% of all newly diagnosed breast cancers. A major barrier to improving clinical outcomes in breast cancer is drug resistance. Drug resistance in breast cancer can be either de novo or acquired following selection pressure from drug treatment. The discovery of the activity of CDK 4 and CDK6 inhibition against HR+ breast cancer has been a significant therapeutic advance. Numerous mechanisms of drug resistance have been proposed, including retinoblastoma gene mutation[3], increased CDK2 activity[4], activation of FGF/FGFR1 signaling[5], basal-like intrinsic breast cancer phenotype[6], YAP (yes-associated protein-1) activation via the Hippo pathway[7], and sequestration of CDK4/6 inhibitors into tumor cell lysosomes[8]. In HER2+ breast cancer, the advent of HER2-directed antibody-drug conjugates (ADCs) has revolutionized treatment, with improvements in both progression-free and overall survival in metastatic diseases and invasive disease-free survival in patients with residual disease following neoadjuvant HER2-targeted therapy[9,10]. Recently, Tsui and colleagues used CRISPR-Cas9 screens to identify genes that control the toxicity of ADCs. Their results demonstrate critical roles for a range of known and novel endolysosomal trafficking regulators in ADC toxicity. In particular, they identified and characterized C18orf8/RMC1 as a regulator of ADC toxicity through its role in endosomal maturation[11]. Finally, triple-negative breast cancer (TNBC), accounting for ~15% of all breast cancers, lacks the classical therapeutic targets of steroid hormone receptors and HER2. Therefore, chemotherapy remains a mainstay of treatment. Mechanisms of chemotherapy resistance in TNBC have been characterized previously[12]. However, at present, significant efforts are underway to integrate immunotherapeutic approaches with PD-(L)1 checkpoint antibodies, along with chemotherapy, as a treatment for TNBC[13,14]. In melanoma and non-small cell lung cancer, a myriad of mechanisms have been offered to explain clinical resistance to immune checkpoint therapeutic antibodies, but the phenomenon of resistance to immune checkpoint inhibition in breast cancer is less well studied. In this special issue of Cancer Drug Resistance, we will discuss the molecular mechanisms of targeted therapy resistance in breast cancers. It is hoped that this issue will suggest future opportunities to overcome targeted therapy resistance in breast cancer, leading ultimately to the goal of eradicating the disease.

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Submission Deadline

28 Feb 2022

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Submission Deadline: 28 Feb 2022
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