The Root Cause of Drug Resistance in HER2-positive Breast Cancer and the Therapeutic Approaches to Overcoming the Resistance

Overview

Journal Pharmacol Ther

Specialty Pharmacology

Date 2020 Sep 8

PMID 32898548

Citations 23

Authors

Yuesheng Zhang

Affiliations

Soon will be listed here.

Abstract

HER2 is a well-known oncogenic receptor tyrosine kinase. HER2 gene amplification occurs in about 20% of breast cancer (BC), which leads to overexpression of HER2 protein, known as HER2-positive BC. Inhibitors of HER2 have significantly improved the prognosis of patients with this subset of BC. Since 1998, seven HER2 inhibitors have been developed to treat this disease. However, drug resistance is common and remains a major unresolved clinical problem. Patients typically show disease progression after some time on treatment. This review discusses the complexity and diversified nature of HER2 signaling, the mechanisms of actions and therapeutic activities of all HER2 inhibitors, the roles of HER2 and other signaling proteins in HER2-positive BC resistant to the inhibitors, the non-cell-autonomous mechanisms of drug resistance, and the heterogeneity of tumor HER2 expression. The review presents the concept that drug resistance in HER2-positive BC results primarily from the inability of HER2 inhibitors to deplete HER2. Emerging therapeutics that are promising for overcoming drug resistance are also discussed.

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References

Garcia-Parra J, Dalmases A, Morancho B, Arpi O, Menendez S, Sabbaghi M . Poly (ADP-ribose) polymerase inhibition enhances trastuzumab antitumour activity in HER2 overexpressing breast cancer. Eur J Cancer. 2014; 50(15):2725-34. DOI: 10.1016/j.ejca.2014.07.004. View

Wolff A, Hammond M, Schwartz J, Hagerty K, Allred D, Cote R . American Society of Clinical Oncology/College of American Pathologists guideline recommendations for human epidermal growth factor receptor 2 testing in breast cancer. Arch Pathol Lab Med. 2009; 131(1):18-43. DOI: 10.5858/2007-131-18-ASOCCO. View

Pauletti G, Godolphin W, Press M, Slamon D . Detection and quantitation of HER-2/neu gene amplification in human breast cancer archival material using fluorescence in situ hybridization. Oncogene. 1996; 13(1):63-72. View

Yang L, Li Y, Bhattacharya A, Zhang Y . A recombinant human protein targeting HER2 overcomes drug resistance in HER2-positive breast cancer. Sci Transl Med. 2019; 11(476). PMC: 6409101. DOI: 10.1126/scitranslmed.aav1620. View

Modi S, Saura C, Yamashita T, Park Y, Kim S, Tamura K . Trastuzumab Deruxtecan in Previously Treated HER2-Positive Breast Cancer. N Engl J Med. 2019; 382(7):610-621. PMC: 7458671. DOI: 10.1056/NEJMoa1914510. View

Zervantonakis I, Poskus M, Scott A, Selfors L, Lin J, Dillon D . Fibroblast-tumor cell signaling limits HER2 kinase therapy response via activation of MTOR and antiapoptotic pathways. Proc Natl Acad Sci U S A. 2020; 117(28):16500-16508. PMC: 7368275. DOI: 10.1073/pnas.2000648117. View

Yang L, Li Y, Bhattacharya A, Zhang Y . A plasma proteolysis pathway comprising blood coagulation proteases. Oncotarget. 2016; 7(27):40919-40938. PMC: 5173032. DOI: 10.18632/oncotarget.7261. View

Cuello M, Ettenberg S, Clark A, Keane M, Posner R, Nau M . Down-regulation of the erbB-2 receptor by trastuzumab (herceptin) enhances tumor necrosis factor-related apoptosis-inducing ligand-mediated apoptosis in breast and ovarian cancer cell lines that overexpress erbB-2. Cancer Res. 2001; 61(12):4892-900. View

Finkle D, Quan Z, Asghari V, Kloss J, Ghaboosi N, Mai E . HER2-targeted therapy reduces incidence and progression of midlife mammary tumors in female murine mammary tumor virus huHER2-transgenic mice. Clin Cancer Res. 2004; 10(7):2499-511. DOI: 10.1158/1078-0432.ccr-03-0448. View

10.

Nahta R, Yuan L, Zhang B, Kobayashi R, Esteva F . Insulin-like growth factor-I receptor/human epidermal growth factor receptor 2 heterodimerization contributes to trastuzumab resistance of breast cancer cells. Cancer Res. 2005; 65(23):11118-28. DOI: 10.1158/0008-5472.CAN-04-3841. View

11.

Clynes R, Towers T, Presta L, Ravetch J . Inhibitory Fc receptors modulate in vivo cytotoxicity against tumor targets. Nat Med. 2000; 6(4):443-6. DOI: 10.1038/74704. View

12.

Goel S, Wang Q, Watt A, Tolaney S, Dillon D, Li W . Overcoming Therapeutic Resistance in HER2-Positive Breast Cancers with CDK4/6 Inhibitors. Cancer Cell. 2016; 29(3):255-269. PMC: 4794996. DOI: 10.1016/j.ccell.2016.02.006. View

13.

Rye I, Trinh A, Saetersdal A, Nebdal D, Lingjaerde O, Almendro V . Intratumor heterogeneity defines treatment-resistant HER2+ breast tumors. Mol Oncol. 2018; 12(11):1838-1855. PMC: 6210052. DOI: 10.1002/1878-0261.12375. View

14.

Choi Y, Li X, Hydbring P, Sanda T, Stefano J, Christie A . The requirement for cyclin D function in tumor maintenance. Cancer Cell. 2012; 22(4):438-51. PMC: 3487466. DOI: 10.1016/j.ccr.2012.09.015. View

15.

Marusyk A, Tabassum D, Janiszewska M, Place A, Trinh A, Rozhok A . Spatial Proximity to Fibroblasts Impacts Molecular Features and Therapeutic Sensitivity of Breast Cancer Cells Influencing Clinical Outcomes. Cancer Res. 2016; 76(22):6495-6506. PMC: 5344673. DOI: 10.1158/0008-5472.CAN-16-1457. View

16.

Bailey T, Luan H, Clubb R, Naramura M, Band V, Raja S . Mechanisms of Trastuzumab resistance in ErbB2-driven breast cancer and newer opportunities to overcome therapy resistance. J Carcinog. 2011; 10:28. PMC: 3243087. DOI: 10.4103/1477-3163.90442. View

17.

Raina D, Uchida Y, Kharbanda A, Rajabi H, Panchamoorthy G, Jin C . Targeting the MUC1-C oncoprotein downregulates HER2 activation and abrogates trastuzumab resistance in breast cancer cells. Oncogene. 2013; 33(26):3422-31. PMC: 3916940. DOI: 10.1038/onc.2013.308. View

18.

Yang L, Li Y, Bhattacharya A, Zhang Y . Inhibition of ERBB2-overexpressing Tumors by Recombinant Human Prolidase and Its Enzymatically Inactive Mutant. EBioMedicine. 2015; 2(5):396-405. PMC: 4465122. DOI: 10.1016/j.ebiom.2015.03.016. View

19.

Slamon D, Clark G, Wong S, Levin W, Ullrich A, McGuire W . Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science. 1987; 235(4785):177-82. DOI: 10.1126/science.3798106. View

20.

Molina M, Saez R, Ramsey E, Garcia-Barchino M, Rojo F, Evans A . NH(2)-terminal truncated HER-2 protein but not full-length receptor is associated with nodal metastasis in human breast cancer. Clin Cancer Res. 2002; 8(2):347-53. View