HER3: Toward the Prognostic Significance, Therapeutic Potential, Current Challenges, and Future Therapeutics in Different Types of Cancer.

Publisher: MDPI Country of Publication: Switzerland NLM ID: 101600052 Publication Model: Electronic Cited Medium: Internet ISSN: 2073-4409 (Electronic) Linking ISSN: 20734409 NLM ISO Abbreviation: Cells Subsets: MEDLINE

Original Publication: Basel, Switzerland : MDPI

Carcinoma, Non-Small-Cell Lung*/metabolism ; Lung Neoplasms*/metabolism; Humans ; Prognosis ; Ligands ; Phosphatidylinositol 3-Kinases/metabolism ; Receptor, ErbB-3/metabolism

Human epidermal growth factor receptor 3 (HER3) is the only family member of the EGRF/HER family of receptor tyrosine kinases that lacks an active kinase domain (KD), which makes it an obligate binding partner with other receptors for its oncogenic role. When HER3 is activated in a ligand-dependent (NRG1/HRG) or independent manner, it can bind to other receptors (the most potent binding partner is HER2) to regulate many biological functions (growth, survival, nutrient sensing, metabolic regulation, etc.) through the PI3K-AKT-mTOR pathway. HER3 has been found to promote tumorigenesis, tumor growth, and drug resistance in different cancer types, especially breast and non-small cell lung cancer. Given its ubiquitous expression across different solid tumors and role in oncogenesis and drug resistance, there has been a long effort to target HER3. As HER3 cannot be targeted through its KD with small-molecule kinase inhibitors via the conventional method, pharmaceutical companies have used various other approaches, including blocking either the ligand-binding domain or extracellular domain for dimerization with other receptors. The development of treatment options with anti-HER3 monoclonal antibodies, bispecific antibodies, and different combination therapies showed limited clinical efficiency for various reasons. Recent reports showed that the extracellular domain of HER3 is not required for its binding with other receptors, which raises doubt about the efforts and applicability of the development of the HER3-antibodies for treatment. Whereas HER3-directed antibody-drug conjugates showed potentiality for treatment, these drugs are still under clinical trial. The currently understood model for dimerization-induced signaling remains incomplete due to the absence of the crystal structure of HER3 signaling complexes, and many lines of evidence suggest that HER family signaling involves more than the interaction of two members. This review article will significantly expand our knowledge of HER3 signaling and shed light on developing a new generation of drugs that have fewer side effects than the current treatment regimen for these patients.

Cancer Res. 2010 Feb 1;70(3):1204-14. (PMID: 20103628)
Cancer Res. 2008 Apr 1;68(7):2340-8. (PMID: 18381441)
Clin Cancer Res. 2006 Jul 1;12(13):4103-11. (PMID: 16818711)
Lung Cancer. 2018 Oct;124:71-75. (PMID: 30268483)
Clin Cancer Res. 2006 Dec 15;12(24):7242-51. (PMID: 17189395)
Sci Transl Med. 2011 Sep 7;3(99):99ra86. (PMID: 21900593)
Sci Rep. 2020 Feb 20;10(1):3009. (PMID: 32080212)
Oncologist. 2019 Aug;24(8):1095-1102. (PMID: 30975923)
Anticancer Drugs. 2012 Sep;23(8):765-76. (PMID: 22824822)
Int J Colorectal Dis. 2009 Sep;24(9):1059-68. (PMID: 19390858)
Cancer Discov. 2022 Jan;12(1):74-89. (PMID: 34548309)
Cancer Res. 2013 Oct 1;73(19):6024-35. (PMID: 23928993)
Int J Cancer. 2012 Mar 1;130(5):1120-7. (PMID: 21484789)
Cancer Chemother Pharmacol. 2017 Jan;79(1):131-138. (PMID: 27942917)
Am J Physiol Cell Physiol. 2018 Nov 1;315(5):C609-C622. (PMID: 30110564)
Oncogene. 2010 Jul 22;29(29):4225-36. (PMID: 20498641)
Cancer Cell. 2015 Mar 9;27(3):397-408. (PMID: 25759024)
Curr Oncol. 2012 Jun;19(Suppl 1):S33-44. (PMID: 22787409)
J Clin Oncol. 2016 Dec 20;34(36):4345-4353. (PMID: 27998236)
Mol Syst Biol. 2005;1:2005.0008. (PMID: 16729043)
Science. 1987 Jan 9;235(4785):177-82. (PMID: 3798106)
J Histochem Cytochem. 2000 Jan;48(1):63-80. (PMID: 10653587)
J Cancer. 2020 Mar 5;11(11):3288-3302. (PMID: 32231734)
Br J Cancer. 1992 Dec;66(6):1116-21. (PMID: 1333787)
Nat Rev Cancer. 2005 May;5(5):341-54. (PMID: 15864276)
Oncogene. 2010 Sep 16;29(37):5193-203. (PMID: 20581867)
Mol Cancer Ther. 2013 Apr;12(4):427-37. (PMID: 23395887)
Cancer Biol Ther. 2011 May 1;11(9):793-800. (PMID: 21307659)
Biochem J. 1998 Aug 1;333 ( Pt 3):757-63. (PMID: 9677338)
Physiology (Bethesda). 2010 Apr;25(2):85-101. (PMID: 20430953)
Mol Cancer Res. 2014 Jun;12(6):940-52. (PMID: 24615340)
Immunol Endocr Metab Agents Med Chem. 2011 Jun;11(2):131-149. (PMID: 21603064)
J Biol Chem. 1996 Feb 16;271(7):3884-90. (PMID: 8632008)
Clin Cancer Res. 2013 Jun 1;19(11):3078-87. (PMID: 23591447)
Cancer Treat Rev. 2018 Jul;68:111-123. (PMID: 29944978)
Curr Oncol. 2012 Jun;19(Suppl 1):S52-8. (PMID: 22787411)
J Clin Oncol. 2011 Aug 1;29(22):3030-6. (PMID: 21709195)
J Cell Physiol. 2004 Sep;200(3):343-50. (PMID: 15254961)
J Biol Chem. 1998 Mar 27;273(13):7717-24. (PMID: 9516479)
Cancer Lett. 1995 Aug 16;95(1-2):79-83. (PMID: 7656248)
Clin Cancer Res. 2018 May 15;24(10):2276-2284. (PMID: 29506988)
Can J Physiol Pharmacol. 2019 Jun;97(6):441-456. (PMID: 30422673)
J Clin Oncol. 2003 Jul 15;21(14):2787-99. (PMID: 12860957)
CA Cancer J Clin. 2022 Jan;72(1):7-33. (PMID: 35020204)
Clin Cancer Res. 2019 Oct 1;25(19):5752-5758. (PMID: 31308059)
Oncogene. 2005 Mar 10;24(11):1847-59. (PMID: 15688028)
Cancer Res. 2002 Jun 1;62(11):3151-8. (PMID: 12036928)
ESMO Open. 2019 Jul 22;4(4):e000532. (PMID: 31423336)
Cancer Res. 2008 Jul 15;68(14):5878-87. (PMID: 18632642)
Oncology. 1998 Mar-Apr;55(2):161-7. (PMID: 9499191)
Ann Oncol. 2018 Jan 1;29(1):170-177. (PMID: 29045543)
J Neurosci. 1995 Feb;15(2):1329-40. (PMID: 7869101)
Endocr Relat Cancer. 2001 Mar;8(1):11-31. (PMID: 11350724)
Nature. 2012 Jan 26;483(7387):100-3. (PMID: 22281684)
FEBS Lett. 2004 Jul 2;569(1-3):332-6. (PMID: 15225657)
Cancer Med. 2019 Mar;8(3):1258-1268. (PMID: 30701699)
Acta Biochim Biophys Sin (Shanghai). 2014 Mar;46(3):190-8. (PMID: 24449784)
Oncotarget. 2015 Jul 10;6(19):16902-11. (PMID: 26160848)
Br J Cancer. 1996 Jul;74(2):229-33. (PMID: 8688326)
Proc Natl Acad Sci U S A. 2015 Jan 20;112(3):839-44. (PMID: 25564668)
Clin Cancer Res. 2007 Aug 15;13(16):4909-19. (PMID: 17699871)
Clin Cancer Res. 2014 Jan 15;20(2):278-80. (PMID: 24240115)
Invest New Drugs. 2018 Oct;36(5):848-859. (PMID: 29349598)
Invest New Drugs. 2021 Dec;39(6):1604-1612. (PMID: 34250553)
Clin Cancer Res. 2019 Jan 15;25(2):487-495. (PMID: 30327312)
Cancer Res. 2010 Mar 15;70(6):2485-94. (PMID: 20215504)
Cancer Sci. 2013 Dec;104(12):1618-25. (PMID: 24112719)
Can J Physiol Pharmacol. 2019 Jun;97(6):463-472. (PMID: 30444648)
J Clin Oncol. 2006 Sep 10;24(26):4317-23. (PMID: 16896008)
Sci Signal. 2009 Jun 30;2(77):ra31. (PMID: 19567914)
N Engl J Med. 2008 Sep 11;359(11):1116-27. (PMID: 18784101)
Oncologist. 2017 Sep;22(9):1024-e89. (PMID: 28592615)
Nat Rev Cancer. 2009 Jul;9(7):463-75. (PMID: 19536107)
Mol Imaging Biol. 2016 Jun;18(3):446-53. (PMID: 26567113)
Oncogene. 2003 May 22;22(21):3205-12. (PMID: 12761490)
Cancer Sci. 2018 Dec;109(12):3774-3782. (PMID: 30259607)
Clin Cancer Res. 2019 Dec 1;25(23):7151-7161. (PMID: 31471314)
Proc Natl Acad Sci U S A. 1991 Sep 1;88(17):7792-6. (PMID: 1715580)
Mol Oncol. 2012 Oct;6(5):516-29. (PMID: 22841590)
Int J Cancer. 2007 May 1;120(9):1874-82. (PMID: 17266042)
Thyroid. 2022 Mar;32(3):273-282. (PMID: 35045748)
Oncogene. 2015 Apr 23;34(17):2215-26. (PMID: 24909175)
Proc Natl Acad Sci U S A. 2009 Dec 22;106(51):21608-13. (PMID: 20007378)
Clin Cancer Res. 2014 Jan 15;20(2):456-68. (PMID: 24097864)
Clin Cancer Res. 2021 Jul 1;27(13):3528-3539. (PMID: 33608318)
Nat Rev Cancer. 2012 Jul 12;12(8):553-63. (PMID: 22785351)
Cancer Res. 2009 Mar 15;69(6):2191-4. (PMID: 19276389)
Exp Cell Res. 2003 Mar 10;284(1):89-98. (PMID: 12648468)
Breast Cancer Res Treat. 2009 Mar;114(2):263-75. (PMID: 18409071)
BioDrugs. 2017 Feb;31(1):63-73. (PMID: 28000159)
Mol Cell Biol. 1996 Oct;16(10):5276-87. (PMID: 8816440)
Clin Cancer Res. 2005 Mar 15;11(6):2163-8. (PMID: 15788662)
Circ Res. 2004 Sep 3;95(5):459-70. (PMID: 15345668)
Gene Ther. 2011 Apr;18(4):326-33. (PMID: 21179173)
Proc Natl Acad Sci U S A. 1989 Dec;86(23):9193-7. (PMID: 2687875)
Nat Commun. 2016 Oct 31;7:13307. (PMID: 27796308)
Signal Transduct Target Ther. 2019 Dec 24;4:64. (PMID: 31885879)
Cancer. 2016 Dec 15;122(24):3803-3811. (PMID: 27525588)
Growth Factors. 2008 Dec;26(6):316-24. (PMID: 18937111)
Clin Cancer Res. 2010 Mar 1;16(5):1373-83. (PMID: 20179223)
Clin Cancer Res. 2006 May 1;12(9):2730-7. (PMID: 16675564)
Invest New Drugs. 2017 Feb;35(1):68-78. (PMID: 27853996)
Am J Respir Cell Mol Biol. 2002 Sep;27(3):306-13. (PMID: 12204892)
Curr Eye Res. 2019 Mar;44(3):287-293. (PMID: 30369271)
J Clin Oncol. 2023 Oct 6;:JCO2300882. (PMID: 37801674)
Nat Med. 2011 Apr;17(4):461-9. (PMID: 21399647)
Clin Cancer Res. 2017 Sep 15;23(18):5406-5415. (PMID: 28600476)
Cancer Cell. 2011 Aug 16;20(2):158-72. (PMID: 21840482)
Antioxidants (Basel). 2023 Jul 29;12(8):. (PMID: 37627515)
Biochemistry. 2000 Jul 25;39(29):8503-11. (PMID: 10913256)
J Pathol. 2003 Jul;200(3):290-7. (PMID: 12845624)
Proc Natl Acad Sci U S A. 2017 Apr 4;114(14):E2836-E2845. (PMID: 28320942)
Proc Natl Acad Sci U S A. 2003 Jul 22;100(15):8933-8. (PMID: 12853564)
J Clin Invest. 2013 May;123(5):2155-68. (PMID: 23543055)
Gastric Cancer. 2015 Jul;18(3):476-84. (PMID: 25038874)
Nat Chem Biol. 2014 Dec;10(12):1006-12. (PMID: 25326665)
EMBO J. 1997 Apr 1;16(7):1647-55. (PMID: 9130710)
Br J Cancer. 1998 Nov;78(10):1385-90. (PMID: 9823984)
Biophys J. 2007 Aug 1;93(3):1021-31. (PMID: 17496034)
BMC Cancer. 2017 Sep 12;17(1):646. (PMID: 28899363)
Cancer Sci. 2016 Oct;107(10):1465-1470. (PMID: 27452985)
Eur J Cancer. 2019 Dec;123:36-47. (PMID: 31648099)
J Clin Oncol. 2014 Dec 10;32(35):4012-9. (PMID: 25385727)
Elife. 2016 Mar 28;5:. (PMID: 27017828)
Nature. 2007 Jan 25;445(7126):437-41. (PMID: 17206155)
Br J Cancer. 2011 Aug 9;105(4):523-33. (PMID: 21792199)
Am J Cancer Res. 2022 May 15;12(5):2249-2276. (PMID: 35693095)
Mol Cell Biol. 1994 Jun;14(6):3550-8. (PMID: 7515147)
Breast Cancer Res. 2013;15(5):R85. (PMID: 24044505)
Sci Rep. 2015 Nov 05;5:16280. (PMID: 26538233)
Front Oncol. 2016 Oct 31;6:232. (PMID: 27843803)
Gynecol Oncol. 2005 Nov;99(2):415-21. (PMID: 16157365)
Clin Cancer Res. 2016 Feb 15;22(4):877-85. (PMID: 26463709)
Clin Cancer Res. 2008 Dec 1;14(23):7843-9. (PMID: 19047113)
BMC Cancer. 2006 Feb 28;6:46. (PMID: 16507107)
Clin Cancer Res. 2005 Jul 1;11(13):4835-42. (PMID: 16000581)
Cancer Res. 2003 Jul 1;63(13):3764-74. (PMID: 12839972)
Clin Cancer Res. 2012 Feb 15;18(4):956-68. (PMID: 22142822)
Breast Cancer Res. 2011 Mar 11;13(2):R29. (PMID: 21396094)
Cancer Discov. 2018 Jun;8(6):686-695. (PMID: 29610121)
Cell Rep. 2022 Feb 1;38(5):110285. (PMID: 35108526)
Hum Pathol. 1998 Aug;29(8):771-7. (PMID: 9712416)
Breast Cancer Res Treat. 2012 Apr;132(2):463-70. (PMID: 21638049)
Clin Cancer Res. 2015 Jun 1;21(11):2462-70. (PMID: 26034219)
Oncogene. 1995 May 4;10(9):1813-21. (PMID: 7538656)
Physiol Rep. 2018 Sep;6(17):e13858. (PMID: 30175474)
J Clin Invest. 2020 Jan 2;130(1):374-388. (PMID: 31661465)
Cancer Cell. 2020 Aug 10;38(2):279-296.e9. (PMID: 32679108)
J Nucl Med. 2019 Jul;60(7):902-909. (PMID: 30733323)
Eur J Cancer. 2002 May;38(8):1065-71. (PMID: 12008194)
Clin Cancer Res. 2012 Dec 15;18(24):6784-91. (PMID: 23092874)
Ann Oncol. 2008 Jan;19(1):73-80. (PMID: 17962208)
Nature. 2012 Jul 26;487(7408):505-9. (PMID: 22763448)
Science. 2007 May 18;316(5827):1039-43. (PMID: 17463250)
Eur J Cancer. 2007 Nov;43(17):2602-11. (PMID: 17920261)
Cancer Cell. 2011 Oct 18;20(4):423-5. (PMID: 22014569)
Oncology. 2011;81(3-4):192-8. (PMID: 22067729)
EMBO J. 1994 Jun 15;13(12):2831-41. (PMID: 8026468)
Int J Cancer. 2006 Dec 15;119(12):2986-7. (PMID: 16998794)
Breast Cancer Res. 2004;6(3):R246-51. (PMID: 15084248)
Sci Transl Med. 2013 Jul 31;5(196):196ra99. (PMID: 23903756)
J Biol Chem. 2010 Dec 10;285(50):39481-9. (PMID: 20940297)
Cancer Biol Ther. 2010 Sep 15;10(6):555-63. (PMID: 20647770)
Mol Cancer Ther. 2020 Feb;19(2):490-501. (PMID: 31911530)
Proc Natl Acad Sci U S A. 2010 Apr 27;107(17):7692-7. (PMID: 20351256)
J Biol Chem. 1998 Aug 14;273(33):20996-1002. (PMID: 9694850)
J Transl Med. 2011 Jul 29;9:126. (PMID: 21801427)
Oncogene. 2000 Nov 20;19(49):5548-57. (PMID: 11114734)
MAbs. 2011 Mar-Apr;3(2):133-52. (PMID: 21304271)
Histopathology. 1994 Sep;25(3):247-52. (PMID: 7821892)
Proc Natl Acad Sci U S A. 1990 Jul;87(13):4905-9. (PMID: 2164210)
Sci Rep. 2021 Apr 27;11(1):9091. (PMID: 33907275)
Oncoimmunology. 2017 Apr 12;6(6):e1315495. (PMID: 28680745)
J Biol Chem. 2010 Feb 26;285(9):6770-80. (PMID: 20026598)
Development. 1997 Dec;124(24):4999-5011. (PMID: 9362461)
Cancer Gene Ther. 2008 Jul;15(7):413-48. (PMID: 18404164)
Ann Oncol. 2020 Jan;31(1):79-87. (PMID: 31912800)
Exp Eye Res. 2018 Sep;174:80-92. (PMID: 29803556)
Clin Cancer Res. 2008 Aug 15;14(16):5188-97. (PMID: 18698037)

Keywords: antibody–drug conjugate (ADC); breast cancer; epidermal growth factor receptor (EGFR); human epidermal growth factor receptor 2 (HER2); monoclonal antibody; non-small cell lung cancers (NSCLC); small-molecule inhibitors; structure-function analyses; targeted therapy

0 (Ligands)
EC 2.7.1.- (Phosphatidylinositol 3-Kinases)
EC 2.7.10.1 (Receptor, ErbB-3)

Date Created: 20231110 Date Completed: 20231113 Latest Revision: 20240201

20240202

PMC10648638

10.3390/cells12212517

37947595