Katie De Jong

Background: Breast cancer is the second most common cancer worldwide and the most frequently diagnosed female cancer, with one in eight women being diagnosed with breast cancer.¹ BRCA 1 and BRCA 2, loss-of-function mutations for two genes that are crucial in DNA damage response, are found in 30% of patients with a family history of breast or ovarian cancer.³ Women who are carriers of the BRCA gene have a significantly increased risk of developing breast cancer.³ Currently, treatment options for breast cancer include surgery and chemotherapy, depending on tumor size, hormone sensitivity, histological markers, presence of metastasis, patient age, and patient preference.¹ Poly (ADP-ribose) polymerase (PARP) inhibitors have been used to specifically target BRCA deficient breast cancer cells, however, many women ultimately develop acquired resistance to these inhibiting drugs.² In efforts to overcome this resistance, manipulation of the STING pathway has been shown to be a promising therapeutic approach to sensitizing PARP inhibitors.^6-10 These findings could suggest a new combination therapy option for BRCA deficient breast cancer.

Objectives:  In this narrative review, we explored the mechanisms by which STING agonism enhances the sensitivity of PARP inhibitors in the treatment of BRCA deficient breast cancer.

Search Methods: An online search in the PubMed database was conducted from 2018 to 2023 using the following keywords: “breast cancer”, ” BRCA”, ” PARP inhibitor resistance”, ” STING agonist”.

Results: Studies have shown that PARP inhibitors have the ability to activate the STING pathway.⁶ When CRISPR/Cas9 control and STING-depleted tumors were treated with Olaparib, STING depletion resulted in abolished PARP inhibitor-induced TBK1 phosphorylation and upregulation of IFNβ, CCL5 and CXCL10 mRNA levels.⁶ Olaparib also significantly increased the CD8 T cell and granzyme B production in CRISPR/Cas9 control tumors, while CD8 T cell and granzyme B production was abolished in STING KO tumors, indicating that activation of the STING pathway and the resulting production of type 1 IFNs in response to PARP inhibition is needed for recruitment of CD8 T cells and anti-tumor immune response.⁶ To further investigate the role of the STING pathway in PARP inhibitor treatment, in K14-Cre-Brca1f/f;Trp53f/f tumors treated with Olaparib, ADU-S100 (STING agonist) or the combination.⁷ The combination treatment showed elevated IFNβ mRNA levels, increased antigen presentation ability of dendritic cells, and an increase in T cell counts.⁷ The combination therapy also showed significantly reduced tumor growth and an inability for tumors to re-established compared to Olaparib monotherapy.⁷ DMXAA (STING agonist) in combination with Olaparib showed similar ability to suppress tumor growth, increase production of anti-tumor cytokines (IFNγ, Granzyme B, and TNFα), as well as stimulate anti-tumorigenic M1 associated genes.⁹

Conclusion: Studies have found that STING agonism potentiates the anti-tumor efficacy of PARP inhibitors. The combination therapy of PARP inhibitors and STING agonism helps overcome PARPi resistance and contributes to immunologic memory in BRCA-deficient mice. The strong preclinical therapeutic efficacy of combined STING agonism and PARP inhibition justifies further development of this therapy as a treatment for BRCA-deficient tumors.

Work Cited:

1. Watkins, Elyse J. DHSc, PA-C, DFAAPA. Overview of breast cancer. Journal of the American Academy of Physician Assistants 32(10):p 13-17. Published 2019 Oct. doi: 10.1097/01.JAA.0000580524.95733.3d.
2. Li H, Liu ZY, Wu N, Chen YC, Cheng Q, Wang J. PARP inhibitor resistance: the underlying mechanisms and clinical implications. Mol Cancer. 2020;19(1):107. Published 2020 Jun 20. doi:10.1186/s12943-020-01227-0.
3. Cortesi L, Rugo HS, Jackisch C. An Overview of PARP Inhibitors for the Treatment of Breast Cancer. Target Oncol. 2021;16(3):255-282. doi:10.1007/s11523-021-00796-4.
4. DeSantis, C.E., Ma, J., Goding Sauer, A., Newman, L.A. and Jemal, A., Breast cancer statistics, 2017, racial disparity in mortality by state. CA: A Cancer Journal for Clinicians, 67: 439-448, 2017;67(6):439-448.
5. Yamaguchi H, Du Y, Nakai K, et al. EZH2 contributes to the response to PARP inhibitors through its PARP-mediated poly-ADP ribosylation in breast cancer. Oncogene. 2018;37(2):208-217. doi:10.1038/onc.2017.311
6. Pantelidou C, Sonzogni O, De Oliveria Taveira M, et al. PARP Inhibitor Efficacy Depends on CD8+ T-cell Recruitment via Intratumoral STING Pathway Activation in BRCA-Deficient Models of Triple-Negative Breast Cancer. Cancer Discov. 2019;9(6):722-737. doi:10.1158/2159-8290.CD-18-1218
7. Pantelidou C, Jadhav H, Kothari A, et al. STING agonism enhances anti-tumor immune responses and therapeutic efficacy of PARP inhibition in BRCA-associated breast cancer. NPJ Breast Cancer. 2022;8(1):102. Published 2022 Sep 6. doi:10.1038/s41523-022-00471-5
8. Milling LE, Garafola D, Agarwal Y, et al. Neoadjuvant STING Activation, Extended Half-life IL2, and Checkpoint Blockade Promote Metastasis Clearance via Sustained NK-cell Activation. Cancer Immunol Res. 2022;10(1):26-39. doi:10.1158/2326-6066.CIR-21-0247
9. Wang Q, Bergholz JS, Ding L, et al. STING agonism reprograms tumor-associated macrophages and overcomes resistance to PARP inhibition in BRCA1-deficient models of breast cancer. Nat Commun. 2022;13(1):3022. Published 2022 May 31. doi:10.1038/s41467-022-30568-1
10. Decout, A., Katz, J.D., Venkatraman, S. et al. The cGAS–STING pathway as a therapeutic target in inflammatory diseases. Nat Rev Immunol 21, 548–569 (2021). https://doi.org/10.1038/s41577-021-00524-z