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HER3 upregulation reduces DS-8201 sensitivity in HER2-positive tumor cells by ATR/CHK1/FoxO1 signaling cascade

Acta Pharmacologica Sinica (2025)Cite this article

Abstract

The anti-HER2 antibody‒drug conjugate (ADC) DS-8201 presents new hope for patients with advanced HER2-positive tumors. Its clinical application, however, is hindered by serious adverse reactions and reduced efficacy following long-term treatment. In this study, we investigated the factors influencing the sensitivity of DS-8201 and developed effective combination regimens to optimize its therapeutic efficacy. We showed that HER3 upregulation diminished the sensitivity of HER2-positive tumor cells to DS-8201. We found that DS-8201 treatment activated DNA damage repair responses in BT-474 cells, in which the ATR kinase pathway induced the expression of the HER3 transcription factor FoxO1, leading to increased HER3 levels. This process was triggered by the payload component of DS-8201, the topoisomerase I inhibitor DXd, rather than the antibody. Based on this finding, we showed that combining DS-8201 with either a HER3-targeting antibody (SIBP-03) or an ATR inhibitor (BAY1895344) resulted in significant synergistic antitumor efficacy without substantial toxicity in vitro or in vivo. Overall, this study revealed that the ATR/FoxO1/HER3 pathway plays a critical role in modulating the efficacy of DS-8201, suggesting that combining DS-8201 with ATR or HER3 inhibition represents a promising therapeutic strategy for HER2-positive cancers.

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Fig. 1: HER3 inhibition potentiates DS-8201 efficacy in HER2-positive cancers.
Fig. 2: HER3 is upregulated upon DS-8201 treatment.
Fig. 3: DS-8201-induced HER3 expression is mediated by FoxO1.
Fig. 4: The ATR/CHK1 axis mediates DS-8201-induced FoxO1/HER3 upregulation.
Fig. 5: Inhibition of ATR/HER3 enhances the activity of DS-8201 in HER2-positive cancer cells.
Fig. 6: Both HER3 blockade and ATR inhibition enhance DS-8201 efficacy in vivo.
Fig. 7: Mechanism underlying HER3-mediated insensitivity to DS-8201.

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References

  1. Sheng Q, Liu J. The therapeutic potential of targeting the EGFR family in epithelial ovarian cancer. Br J Cancer. 2011;104:1241–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Graus-Porta D, Beerli RR, Daly JM, Hynes NE. ErbB-2, the preferred heterodimerization partner of all ErbB receptors, is a mediator of lateral signaling. EMBO J. 1997;16:1647–55.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Roskoski R Jr. The ErbB/HER family of protein-tyrosine kinases and cancer. Pharmacol Res. 2014;79:34–74.

    Article  CAS  PubMed  Google Scholar 

  4. Oh DY, Bang YJ. HER2-targeted therapies - a role beyond breast cancer. Nat Rev Clin Oncol. 2020;17:33–48.

    Article  CAS  PubMed  Google Scholar 

  5. Sidaway P. T-DXd is effective after T-DM1. Nat Rev Clin Oncol. 2023;20:426.

    CAS  PubMed  Google Scholar 

  6. Nakada T, Sugihara K, Jikoh T, Abe Y, Agatsuma T. The latest research and development into the antibody-drug conjugate, [fam-] trastuzumab deruxtecan (DS-8201a), for HER2 cancer therapy. Chem Pharm Bull (Tokyo). 2019;67:173–85.

    Article  CAS  PubMed  Google Scholar 

  7. Yver A, Agatsuma T, Soria JC. The art of innovation: clinical development of trastuzumab deruxtecan and redefining how antibody-drug conjugates target HER2-positive cancers. Ann Oncol. 2020;31:430–4.

    Article  CAS  PubMed  Google Scholar 

  8. Modi S, Jacot W, Yamashita T, Sohn J, Vidal M, Tokunaga E, et al. Trastuzumab deruxtecan in previously treated HER2-low advanced breast cancer. N Engl J Med. 2022;387:9–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Li BT, Smit EF, Goto Y, Nakagawa K, Udagawa H, Mazières J, et al. Trastuzumab deruxtecan in HER2-mutant non-small-cell lung cancer. N Engl J Med. 2022;386:241–51.

    Article  CAS  PubMed  Google Scholar 

  10. Doi T, Shitara K, Naito Y, Shimomura A, Fujiwara Y, Yonemori K, et al. Safety, pharmacokinetics, and antitumour activity of trastuzumab deruxtecan (DS-8201), a HER2-targeting antibody-drug conjugate, in patients with advanced breast and gastric or gastro-oesophageal tumours: a phase 1 dose-escalation study. Lancet Oncol. 2017;18:1512–22.

    Article  CAS  PubMed  Google Scholar 

  11. Modi S, Saura C, Yamashita T, Park YH, Kim SB, Tamura K, et al. Trastuzumab deruxtecan in previously treated HER2-positive breast cancer. N Engl J Med. 2020;382:610–21.

    Article  CAS  PubMed  Google Scholar 

  12. Papa F, Grinda T, Rassy E, Cheickh-Hussin R, Ribeiro J, Antonuzzo L, et al. Long road towards effective HER3 targeting in breast cancer. Cancer Treat Rev. 2024;129:102786.

    Article  CAS  PubMed  Google Scholar 

  13. Pan L, Li J, Xu Q, Gao Z, Yang M, Wu X, et al. HER2/PI3K/AKT pathway in HER2-positive breast cancer: A review. Med (Balt). 2024;103:e38508.

    Article  CAS  Google Scholar 

  14. Vaught DB, Stanford JC, Young C, Hicks DJ, Wheeler F, Rinehart C, et al. HER3 is required for HER2-induced preneoplastic changes to the breast epithelium and tumor formation. Cancer Res. 2012;72:2672–82.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Lee-Hoeflich ST, Crocker L, Yao E, Pham T, Munroe X, Hoeflich KP, et al. A central role for HER3 in HER2-amplified breast cancer: implications for targeted therapy. Cancer Res. 2008;68:5878–87.

    Article  CAS  PubMed  Google Scholar 

  16. Watanabe S, Yonesaka K, Tanizaki J, Nonagase Y, Takegawa N, Haratani K, et al. Targeting of the HER2/HER3 signaling axis overcomes ligand-mediated resistance to trastuzumab in HER2-positive breast cancer. Cancer Med. 2019;8:1258–68.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Chen X, Liu P, Wang Q, Li Y, Fu L, Fu H, et al. DCZ3112, a novel Hsp90 inhibitor, exerts potent antitumor activity against HER2-positive breast cancer through disruption of Hsp90-Cdc37 interaction. Cancer Lett. 2018;434:70–80.

    Article  CAS  PubMed  Google Scholar 

  18. Li WJ, Xie CY, Zhu X, Tang J, Wang L, Lou LG. SIBP-03, a novel anti-HER3 antibody, exerts antitumor effects and synergizes with EGFR- and HER2-targeted drugs. Acta Pharmacol Sin. 2024;45:857–66.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Kumagai S, Koyama S, Nishikawa H. Antitumour immunity regulated by aberrant ERBB family signalling. Nat Rev Cancer. 2021;21:181–97.

    Article  CAS  PubMed  Google Scholar 

  20. Yonesaka K, Tanizaki J, Maenishi O, Haratani K, Kawakami H, Tanaka K, et al. HER3 augmentation via blockade of EGFR/AKT signaling enhances anticancer activity of HER3-targeting patritumab deruxtecan in EGFR-mutated non-small cell lung cancer. Clin Cancer Res. 2022;28:390–403.

    Article  CAS  PubMed  Google Scholar 

  21. Hanker AB, Brown BP, Meiler J, Marín A, Jayanthan HS, Ye D, et al. Co-occurring gain-of-function mutations in HER2 and HER3 modulate HER2/HER3 activation, oncogenesis, and HER2 inhibitor sensitivity. Cancer Cell. 2021;39:1099–1114.e8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Cervantes-Gomez F, Nimmanapalli R, Gandhi V. Transcription inhibition of heat shock proteins: a strategy for combination of 17-allylamino-17-demethoxygeldanamycin and actinomycin d. Cancer Res. 2009;69:3947–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Sobell HM. Actinomycin and DNA transcription. Proc Natl Acad Sci USA. 1985;82:5328–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Takahashi S, Karayama M, Takahashi M, Watanabe J, Minami H, Yamamoto N, et al. Pharmacokinetics, safety, and efficacy of trastuzumab deruxtecan with concomitant ritonavir or itraconazole in patients with HER2-expressing advanced solid tumors. Clin Cancer Res. 2021;27:5771–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Tsurutani J, Iwata H, Krop I, Jänne PA, Doi T, Takahashi S, et al. Targeting HER2 with trastuzumab deruxtecan: a dose-expansion, phase I study in multiple advanced solid tumors. Cancer Discov 2020;10:1078. Corrected and republished from: Cancer Discov. 2020; 10: 688-701.

    Article  Google Scholar 

  26. Pilié PG, Tang C, Mills GB, Yap TA. State-of-the-art strategies for targeting the DNA damage response in cancer. Nat Rev Clin Oncol. 2019;16:81–104.

    Article  PubMed  PubMed Central  Google Scholar 

  27. Lee HJ, Lan L, Peng G, Chang WC, Hsu MC, Wang YN, et al. Tyrosine 370 phosphorylation of ATM positively regulates DNA damage response. Cell Res. 2015;25:225–36.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Liccardi G, Hartley JA, Hochhauser D. EGFR nuclear translocation modulates DNA repair following cisplatin and ionizing radiation treatment. Cancer Res. 2011;71:1103–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Yan Y, Hein AL, Greer PM, Wang Z, Kolb RH, Batra SK, et al. A novel function of HER2/Neu in the activation of G2/M checkpoint in response to γ-irradiation. Oncogene. 2015;34:2215–26.

    Article  CAS  PubMed  Google Scholar 

  30. Francis DM, Huang S, Armstrong EA, Werner LR, Hullett C, Li C, et al. Pan-HER inhibitor augments radiation response in human lung and head and neck cancer models. Clin Cancer Res. 2016;22:633–43.

    Article  CAS  PubMed  Google Scholar 

  31. Tan L, Zhang J, Wang Y, Wang X, Wang Y, Zhang Z, et al. Development of dual inhibitors targeting epidermal growth factor receptor in cancer therapy. J Med Chem. 2022;65:5149–83.

    Article  CAS  PubMed  Google Scholar 

  32. Austin CD, De Mazière AM, Pisacane PI, van Dijk SM, Eigenbrot C, Sliwkowski MX, et al. Endocytosis and sorting of ErbB2 and the site of action of cancer therapeutics trastuzumab and geldanamycin. Mol Biol Cell. 2004;15:5268–82.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Narayan M, Wilken JA, Harris LN, Baron AT, Kimbler KD, Maihle NJ. Trastuzumab-induced HER reprogramming in “resistant” breast carcinoma cells. Cancer Res. 2009;69:2191–4.

    Article  CAS  PubMed  Google Scholar 

  34. Gijsen M, King P, Perera T, Parker PJ, Harris AL, Larijani B, et al. HER2 phosphorylation is maintained by a PKB negative feedback loop in response to anti-HER2 herceptin in breast cancer. PLoS Biol. 2016;14:e1002414. Corrected and republished from: PLoS Biol. 2010;8:e1000563.

    Article  PubMed  PubMed Central  Google Scholar 

  35. Schwarz LJ, Hutchinson KE, Rexer BN, Estrada MV, Gonzalez Ericsson PI, Sanders ME, et al. An ERBB1-3 neutralizing antibody mixture with high activity against drug-resistant HER2+ breast cancers with ERBB ligand overexpression. J Natl Cancer Inst. 2017;109:djx065.

    Article  PubMed  PubMed Central  Google Scholar 

  36. Dent RA, Cescon DW, Bachelot T, Jung KH, Shao ZM, Saji S, et al. TROPION-Breast02: datopotamab deruxtecan for locally recurrent inoperable or metastatic triple-negative breast cancer. Future Oncol. 2023;19:2349–59.

    Article  CAS  PubMed  Google Scholar 

  37. Okamoto I, Kuyama S, Girard N, Lu S, Franke F, Li Z, et al. TROPION-Lung07: phase III study of Dato-DXd + pembrolizumab ± platinum-based chemotherapy as 1L therapy for advanced non-small-cell lung cancer. Future Oncol. 2024;20:2927–36.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Jänne PA, Baik C, Su WC, Johnson ML, Hayashi H, Nishio M, et al. Efficacy and safety of patritumab deruxtecan (HER3-DXd) in EGFR inhibitor-resistant, EGFR-mutated non-small cell lung cancer. Cancer Discov. 2022;12:74–89.

    Article  PubMed  Google Scholar 

  39. Yu HA, Baik C, Kim DW, Johnson ML, Hayashi H, Nishio M, et al. Translational insights and overall survival in the U31402-A-U102 study of patritumab deruxtecan (HER3-DXd) in EGFR-mutated NSCLC. Ann Oncol. 2024;35:437–47.

    Article  CAS  PubMed  Google Scholar 

  40. Suzuki H, Nagase S, Saito C, Takatsuka A, Nagata M, Honda K, et al. Raludotatug deruxtecan, a CDH6-targeting antibody-drug conjugate with a DNA topoisomerase I inhibitor DXd, is efficacious in human ovarian and kidney cancer models. Mol Cancer Ther. 2024;23:257–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Trinder A, Ding K, Zhang J. The therapeutic significance of HER3 in non-small cell lung cancer (NSCLC): a review study. Curr Med Chem. 2025;32:434–46.

    Article  CAS  PubMed  Google Scholar 

  42. Zhou KI, Strickler JH, Chen H. Targeting Claudin-18.2 for cancer therapy: updates from 2024 ASCO annual meeting. J Hematol Oncol. 2024;17:73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Bardia A, Mayer IA, Vahdat LT, Tolaney SM, Isakoff SJ, Diamond JR, et al. Sacituzumab govitecan-hziy in refractory metastatic triple-negative breast cancer. N Engl J Med. 2019;380:741–51.

    Article  CAS  PubMed  Google Scholar 

  44. Dormann C. Metastatic human epidermal growth factor receptor 2-positive breast cancer: current treatment standards and future perspectives. Breast Care (Basel). 2020;15:570–8.

    Article  PubMed  Google Scholar 

  45. Crystal RG, Gadek JE, Ferrans VJ, Fulmer JD, Line BR, Hunninghake GW. Interstitial lung disease: current concepts of pathogenesis, staging and therapy. Am J Med. 1981;70:542–68.

    Article  CAS  PubMed  Google Scholar 

  46. Tarantino P, Modi S, Tolaney SM, Cortés J, Hamilton EP, Kim SB, et al. Interstitial lung disease induced by anti-ERBB2 antibody-drug conjugates: A review. JAMA Oncol. 2021;7:1873–81.

    Article  PubMed  Google Scholar 

  47. Kumagai K, Aida T, Tsuchiya Y, Kishino Y, Kai K, Mori K. Interstitial pneumonitis related to trastuzumab deruxtecan, a human epidermal growth factor receptor 2-targeting Ab-drug conjugate, in monkeys. Cancer Sci. 2020;111:4636–45.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Blackford AN, Jackson SP. ATM, ATR, and DNA-PK: the trinity at the heart of the DNA damage response. Mol Cell. 2017;66:801–17.

    Article  CAS  PubMed  Google Scholar 

  49. Zhang C, Chen L, Xie C, Wang F, Wang J, Zhou H, et al. YTHDC1 delays cellular senescence and pulmonary fibrosis by activating ATR in an m6A-independent manner. EMBO J. 2024;43:61–86.

    Article  PubMed  Google Scholar 

  50. Heumann TR, Stockton S, Cecchini M, Aljumaily R, Shyr C, Whisenant J, et al. A phase I study of irinotecan combined with BAY1895344 (ATR inhibitor) in advanced solid tumors: Results of ETCTN 10402 dose escalation. J Clin Oncol. 2024;42:3077.

    Article  Google Scholar 

  51. Stockton S, Shyr C, Cecchini M, Aljumaily R, Halfdanarson TR, Sonbol MB, et al. A phase I study of ATR inhibitor BAY1895344 (elimusertib) plus topotecan (ETCTN 10402): results of dose escalation. J Clin Oncol. 2024;42:3076.

    Article  Google Scholar 

  52. Takahashi N, Hao Z, Villaruz LC, Zhang J, Ruiz J, Petty WJ, et al. Berzosertib plus topotecan vs topotecan alone in patients with relapsed small cell lung cancer: a randomized clinical trial. JAMA Oncol. 2023;9:1669–77.

    Article  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

This research was supported by grants from the Science and Technology Commission of Shanghai Municipality (grant No. 18DZ2293200). The graphical abstract in this manuscript was created with BioGDP.com.

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Authors and Affiliations

  1. Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China

    Wen-jing Li, Kai-ge Kang, Yu-xiang Zhang, Xi Zhu, Jiao Tang, Yong-peng Li, Hao-yu Fu, Qing Yao, Lei Wang & Li-guang Lou

  2. University of Chinese Academy of Sciences, Beijing, 100049, China

    Wen-jing Li, Kai-ge Kang, Yu-xiang Zhang & Li-guang Lou

  3. School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, 210023, China

    Xin-xin Zhao & Li-guang Lou

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Contributions

LGL conceived and designed the research. WJL performed experiments and prepared the figures and manuscript. KGK and YXZ performed part of the cell experiments. WJL, KGK, YXZ, and XXZ contributed to the acquisition and analysis of the data. XZ, JT, and YPL helped with the data analysis and validation. HYF and QY participated in the mouse experiments. LW and LGL revised and approved the manuscript. All authors approved the final manuscript.

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Correspondence to Lei Wang or Li-guang Lou.

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Li, Wj., Kang, Kg., Zhang, Yx. et al. HER3 upregulation reduces DS-8201 sensitivity in HER2-positive tumor cells by ATR/CHK1/FoxO1 signaling cascade. Acta Pharmacol Sin (2025). https://doi.org/10.1038/s41401-025-01647-y

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