1. Secondary mutations in RAD51C and RAD51D Restore HR and Make Cells Resistant to PARPi in Ovarian Carcinoma

Olga Kondrashova et al., June 2017, Cancer Discovery


Poly (Adenosine diphosphate [ADP]) ribose polymerase (PARP) inhibitors (PARPi) is commonly used to treat ovarian cancer caused by BRCA 1/2 mutation. In this article, they investigated if secondary mutation  of other genes other than BRCA 1/2 are involved in PARPi rucaparib (anticancer reagent) resistance.

PARPi : rucaprib, olaparib, niraparib, talazoparib, veliparib
Platinum compounds: cisplatin, carboplatin

12 samples used for biopsy were obtained from before and after tumor progression. 6 out of 12 were found to contain mutation of BRCA1, RAD51C, or RAD51D, which are DNA repair genes. However, 5 out of 6 were found to have secondary 2nd mutation that restore the open reading frame.

4 different 2nd mutation of RAD51C and RAD51D during PARPi treatment. 2nd mutation of RAD51C restores the function of RAD51C KO in ovarian cancer cells, evidenced by
     - Increased HR
     - Restored binding ability of RAD51C to RAD51B and XRCC3
     - Increased resistance to Platinum and PARP inhibitors

CDK12 impacts the normal transcription of HR genes.

Primary cancer cells have 3 copies of primary RAD51C mutation. While cells acquired  resistant have 2 copies of the primary mutation and 1 copy of any 4 of the 2nd mutations. They are not sure which of these copies is functional bc of limited biopsy material.

The PDX tumor models are established from the transplantation of fresh human tumor specimen from a cancer patient directly into a mouse.

Lys residue replacing the Ser-Gly-Arg in RAD51D maintains the interactions with dsDNA .

Mutations in RAD51C or RAD51D are lethal with PARP inhibition, and that 2nd mutations are needed to be resistant to PARPi in non-BRCA1/2 genes.

=> Primary mutations of RAD51C and RAD51D make cells sensitive to PARPi but secondary mutations in these genes help cells more resistant to PARPi.