The DNA Repair Pathway As a Therapeutic Target to Synergize with Trastuzumab Deruxtecan in HER2-targeted Antibody-drug Conjugate-resistant HER2-overexpressing Breast Cancer

Overview

Journal J Exp Clin Cancer Res

Publisher Biomed Central

Specialty Oncology

Date 2024 Aug 20

PMID 39164784

Authors

Jangsoon Lee

Kumiko Kida

Jiwon Koh

Huey Liu

Ganiraju C Manyam

Young Jin Gi

Dileep R Rampa

Asha S Multani

Jing Wang

Gitanjali Jayachandran

Dae-Won Lee

James M Reuben

Aysegul Sahin

Lei Huo

Debu Tripathy

Seock-Ah Im

Naoto T Ueno

Affiliations

Soon will be listed here.

Abstract

Background: Anti-HER2 therapies, including the HER2 antibody-drug conjugates (ADCs) trastuzumab emtansine (T-DM1) and trastuzumab deruxtecan (T-DXd), have led to improved survival outcomes in patients with HER2-overexpressing (HER2+) metastatic breast cancer. However, intrinsic or acquired resistance to anti-HER2-based therapies remains a clinical challenge in these patients, as there is no standard of care following disease progression. The purpose of this study was to elucidate the mechanisms of resistance to T-DM1 and T-DXd in HER2+ BC patients and preclinical models and identify targets whose inhibition enhances the antitumor activity of T-DXd in HER2-directed ADC-resistant HER2+ breast cancer in vitro and in vivo.

Methods: Targeted DNA and whole transcriptome sequencing were performed in breast cancer patient tissue samples to investigate genetic aberrations that arose after anti-HER2 therapy. We generated T-DM1 and T-DXd-resistant HER2+ breast cancer cell lines. To elucidate their resistance mechanisms and to identify potential synergistic kinase targets for enhancing the efficacy of T-DXd, we used fluorescence in situ hybridization, droplet digital PCR, Western blotting, whole-genome sequencing, cDNA microarray, and synthetic lethal kinome RNA interference screening. In addition, cell viability, colony formation, and xenograft assays were used to determine the synergistic antitumor effect of T-DXd combinations.

Results: We found reduced HER2 expression in patients and amplified DNA repair-related genes in patients after anti-HER2 therapy. Reduced ERBB2 gene amplification in HER2-directed ADC-resistant HER2+ breast cancer cell lines was through DNA damage and epigenetic mechanisms. In HER2-directed ADC-resistant HER2+ breast cancer cell lines, our non-biased RNA interference screening identified the DNA repair pathway as a potential target within the canonical pathways to enhance the efficacy of T-DXd. We validated that the combination of T-DXd with ataxia telangiectasia and Rad3-related inhibitor, elimusertib, led to significant breast cancer cell death in vitro (P < 0.01) and in vivo (P < 0.01) compared to single agents.

Conclusions: The DNA repair pathways contribute to HER2-directed ADC resistance. Our data justify exploring the combination treatment of T-DXd with DNA repair-targeting drugs to treat HER2-directed ADC-resistant HER2+ breast cancer in clinical trials.

References

Ogitani Y, Hagihara K, Oitate M, Naito H, Agatsuma T . Bystander killing effect of DS-8201a, a novel anti-human epidermal growth factor receptor 2 antibody-drug conjugate, in tumors with human epidermal growth factor receptor 2 heterogeneity. Cancer Sci. 2016; 107(7):1039-46. PMC: 4946713. DOI: 10.1111/cas.12966. View

Lucking U, Wortmann L, Wengner A, Lefranc J, Lienau P, Briem H . Damage Incorporated: Discovery of the Potent, Highly Selective, Orally Available ATR Inhibitor BAY 1895344 with Favorable Pharmacokinetic Properties and Promising Efficacy in Monotherapy and in Combination Treatments in Preclinical Tumor Models. J Med Chem. 2020; 63(13):7293-7325. DOI: 10.1021/acs.jmedchem.0c00369. View

Chen Y, Xu Y, Shao Z, Yu K . Resistance to antibody-drug conjugates in breast cancer: mechanisms and solutions. Cancer Commun (Lond). 2022; 43(3):297-337. PMC: 10009672. DOI: 10.1002/cac2.12387. View

Subramanian A, Tamayo P, Mootha V, Mukherjee S, Ebert B, Gillette M . Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci U S A. 2005; 102(43):15545-50. PMC: 1239896. DOI: 10.1073/pnas.0506580102. View

Cingolani P, Platts A, Wang L, Coon M, Nguyen T, Wang L . A program for annotating and predicting the effects of single nucleotide polymorphisms, SnpEff: SNPs in the genome of Drosophila melanogaster strain w1118; iso-2; iso-3. Fly (Austin). 2012; 6(2):80-92. PMC: 3679285. DOI: 10.4161/fly.19695. View

Wilm A, Aw P, Bertrand D, Yeo G, Ong S, Wong C . LoFreq: a sequence-quality aware, ultra-sensitive variant caller for uncovering cell-population heterogeneity from high-throughput sequencing datasets. Nucleic Acids Res. 2012; 40(22):11189-201. PMC: 3526318. DOI: 10.1093/nar/gks918. View

Wei Z, Wang W, Hu P, Lyon G, Hakonarson H . SNVer: a statistical tool for variant calling in analysis of pooled or individual next-generation sequencing data. Nucleic Acids Res. 2011; 39(19):e132. PMC: 3201884. DOI: 10.1093/nar/gkr599. View

Wengner A, Siemeister G, Lucking U, Lefranc J, Wortmann L, Lienau P . The Novel ATR Inhibitor BAY 1895344 Is Efficacious as Monotherapy and Combined with DNA Damage-Inducing or Repair-Compromising Therapies in Preclinical Cancer Models. Mol Cancer Ther. 2019; 19(1):26-38. DOI: 10.1158/1535-7163.MCT-19-0019. 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

10.

Barok M, Le Joncour V, Martins A, Isola J, Salmikangas M, Laakkonen P . ARX788, a novel anti-HER2 antibody-drug conjugate, shows anti-tumor effects in preclinical models of trastuzumab emtansine-resistant HER2-positive breast cancer and gastric cancer. Cancer Lett. 2020; 473:156-163. DOI: 10.1016/j.canlet.2019.12.037. View

11.

Rausch T, Zichner T, Schlattl A, Stutz A, Benes V, Korbel J . DELLY: structural variant discovery by integrated paired-end and split-read analysis. Bioinformatics. 2012; 28(18):i333-i339. PMC: 3436805. DOI: 10.1093/bioinformatics/bts378. View

12.

Iwata T, Ishii C, Ishida S, Ogitani Y, Wada T, Agatsuma T . A HER2-Targeting Antibody-Drug Conjugate, Trastuzumab Deruxtecan (DS-8201a), Enhances Antitumor Immunity in a Mouse Model. Mol Cancer Ther. 2018; 17(7):1494-1503. DOI: 10.1158/1535-7163.MCT-17-0749. View

13.

Hurvitz S, Hegg R, Chung W, Im S, Jacot W, Ganju V . Trastuzumab deruxtecan versus trastuzumab emtansine in patients with HER2-positive metastatic breast cancer: updated results from DESTINY-Breast03, a randomised, open-label, phase 3 trial. Lancet. 2022; 401(10371):105-117. DOI: 10.1016/S0140-6736(22)02420-5. View

14.

Collins D, Bossenmaier B, Kollmorgen G, Niederfellner G . Acquired Resistance to Antibody-Drug Conjugates. Cancers (Basel). 2019; 11(3). PMC: 6468698. DOI: 10.3390/cancers11030394. View

15.

Mosele F, Deluche E, Lusque A, Le Bescond L, Filleron T, Pradat Y . Trastuzumab deruxtecan in metastatic breast cancer with variable HER2 expression: the phase 2 DAISY trial. Nat Med. 2023; 29(8):2110-2120. PMC: 10427426. DOI: 10.1038/s41591-023-02478-2. View

16.

Griguolo G, Serna G, Pascual T, Fasani R, Guardia X, Chic N . Immune microenvironment characterisation and dynamics during anti-HER2-based neoadjuvant treatment in HER2-positive breast cancer. NPJ Precis Oncol. 2021; 5(1):23. PMC: 7979716. DOI: 10.1038/s41698-021-00163-6. View

17.

Loganzo F, Tan X, Sung M, Jin G, Myers J, Melamud E . Tumor cells chronically treated with a trastuzumab-maytansinoid antibody-drug conjugate develop varied resistance mechanisms but respond to alternate treatments. Mol Cancer Ther. 2015; 14(4):952-63. DOI: 10.1158/1535-7163.MCT-14-0862. View

18.

Yoon S, Kim S, Nam D . Improving Gene-Set Enrichment Analysis of RNA-Seq Data with Small Replicates. PLoS One. 2016; 11(11):e0165919. PMC: 5102490. DOI: 10.1371/journal.pone.0165919. View

19.

Hurvitz S, Martin M, Jung K, Huang C, Harbeck N, Valero V . Neoadjuvant Trastuzumab Emtansine and Pertuzumab in Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer: Three-Year Outcomes From the Phase III KRISTINE Study. J Clin Oncol. 2019; 37(25):2206-2216. PMC: 6774816. DOI: 10.1200/JCO.19.00882. View

20.

Renwick A, Thompson D, Seal S, Kelly P, Chagtai T, Ahmed M . ATM mutations that cause ataxia-telangiectasia are breast cancer susceptibility alleles. Nat Genet. 2006; 38(8):873-5. DOI: 10.1038/ng1837. View