Mechanism of action of PARPi and other treatments used in HER2-negative breast cancer

How do PARP, CDK4/6 and PD-L1 inhibitors work?

PARP, CDK4/6 and PD-1/PD-L1 inhibitors are targeted therapies indicated for treatment of breast cancers that are human epidermal growth factor receptor 2 (HER2) -negative.¹

PARP inhibitors induce cell death in BRCA-mutated tumors

• Poly-ADP-Ribose Polymerase (PARP) is a key regulator of base excision repair (BER) of DNA single-strand breaks, and plays a role in maintaining genomic stability.^1,2 PARP also has a role in homologous recombination repair (HRR).
• When PARP inhibitors block BER, single-strand breaks are not repaired. This leads to creation of double-strand breaks during DNA replication, which are usually repaired through HRR.¹ In the cells where HRR is dysfunctional, i.e. in cells with BRCA1 or BRCA2 mutation, double-strand breaks are repaired using non-homologous end-joining, which is error-prone and often leads to cell death.¹
• PARP inhibitors target tumor cells with homozygous BRCA1 or BRCA2 mutation and have only minimal effect on normal cells with at least one functional copy of both BRCA genes.²
• Therefore, with the suspected ability to induce cell death in HRR-deficient cells, it is reasonable to use PARP inhibitors in treatment of BRCA-mutated cancers to induce synthetic lethality in tumor cells.^1,2

CDK4/6 inhibitors arrest cell cycle progression and cell proliferation

• Cyclin-dependent kinases (CDKs) regulate the cell cycle.¹
• CDK4 and CDK6 complex with cyclin D, which leads to activation of cell cycle progression from phase G1 onwards.¹
• Cyclin D is overexpressed in hormone receptor (HR) positive breast cancer, resulting in excessive formation of CDK4/6-cyclin D -complexes.^1,3
• Aberrant activation of CDK proteins or cyclin D may result in uncontrolled cell proliferation in tumors.^1,3
• CDK4/6 inhibitors specifically target CDK4 and CDK6, causing arrest of cell cycle and cell proliferation.¹

PD-1/PD-L1 inhibitors increase immune response against tumors

• Programmed cell death protein 1 (PD-1) and programmed cell death ligand 1 (PD-L1) are immune checkpoint proteins that inhibit immune responses.⁴
• Tumor cells can express PD-L1 in order to escape anti-tumor responses of the immune system.
• Immune checkpoint inhibitors, such as PD-1 and PD-L1 inhibitors, aim to increase the immune response, especially by activating cytotoxic T cells against active tumors.¹

References

1. Lau KH, et al. Int J Mol Sci. 2022 Feb 18;23(4):2288.
2. O’Connor MJ. Mol Cell. 2015 Nov 19;60(4):547-60.
3. Chong Q-Y, et al. Pharmacol Res. 2020 Jun;156:104686.
4. Han Y, et al. Am J Cancer Res 2020; Mar 1;10(3):727-742. eCollection 2020.