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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.

References:
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2. Sung, H, Ferlay, J, Siegel, RL, Laversanne, M, Soerjomataram, I, Jemal, A, Bray, F. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2021;71:209- 249.
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7. Li Z, Razavi P, Li Q, Toy W, Liu B, Ping C, Hsieh W, Sanchez-Vega F, Brown DN, Da Cruz Paula AF, Morris L, Selenica P, Eichenberger E, Shen R, Schultz N, Rosen N, Scaltriti M, Brogi E, Baselga J, Reis-Filho JS, Chandarlapaty S. Loss of the FAT1 Tumor Suppressor Promotes Resistance to CDK4/6 Inhibitors via the Hippo Pathway. Cancer Cell 2018;34:893-905.e8.
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10. von Minckwitz G, Huang CS, Mano MS, Loibl S, Mamounas EP, Untch M, Wolmark N, Rastogi P, Schneeweiss A, Redondo A, Fischer HH, Jacot W, Conlin AK, Arce-Salinas C, Wapnir IL, Jackisch C, DiGiovanna MP, Fasching PA, Crown JP, Wülfing P, Shao Z, Rota Caremoli E, Wu H, Lam LH, Tesarowski D, Smitt M, Douthwaite H, Singel SM, Geyer CE Jr; KATHERINE Investigators. Trastuzumab Emtansine for Residual Invasive HER2-Positive Breast Cancer. N Engl J Med 2019;380:617-628.
11. Tsui CK, Barfield RM, Fischer CR, Morgens DW, Li A, Smith BAH, Gray MA, Bertozzi CR, Rabuka D, Bassik MC. CRISPR-Cas9 screens identify regulators of antibody-drug conjugate toxicity. Nat Chem Biol 2019;15:949-958.
12. Echeverria GV, Ge Z, Seth S, Zhang X, Jeter-Jones S, Zhou X, Cai S, Tu Y, McCoy A, Peoples M, Sun Y, Qiu H, Chang Q, Bristow C, Carugo A, Shao J, Ma X, Harris A, Mundi P, Lau R, Ramamoorthy V, Wu Y, Alvarez MJ, Califano A, Moulder SL, Symmans WF, Marszalek JR, Heffernan TP, Chang JT, Piwnica-Worms H. Resistance to neoadjuvant chemotherapy in triple-negative breast cancer mediated by a reversible drug-tolerant state. Sci Transl Med 2019;11:eaav0936.
13. Schmid P, Adams S, Rugo HS, Schneeweiss A, Barrios CH, Iwata H, Diéras V, Hegg R, Im SA, Shaw Wright G, Henschel V, Molinero L, Chui SY, Funke R, Husain A, Winer EP, Loi S, Emens LA; IMpassion130 Trial Investigators. Atezolizumab and Nab-Paclitaxel in Advanced Triple-Negative Breast Cancer. N Engl J Med 2018;379:2108-2121.
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Submission Deadline

28 Feb 2022

Submission Information

Articles of special issue are free of charge for article processing.
For Author Instructions, please refer to http://cdrjournal.com/pages/view/author_instructions
For Online Submission, please login at https://oaemesas.com/login?JournalId=cdr&SpecialIssueId=706
Submission Deadline: 28 Feb 2022
Contacts: Susan Song, Assistant Editor, Susan@cdrjournal.com

Published Articles

This special issue is now open for submission.
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