Cookies on this website
We use cookies to ensure that we give you the best experience on our website. If you click 'Continue' we'll assume that you are happy to receive all cookies and you won't see this message again. Click 'Find out more' for information on how to change your cookie settings.
Skip to main content

Madalena Tarsounas

A conundrum regarding the breast cancer-promoting BRCA1 and BRCA2 gene mutations is that their introduction into normal cells causes cell cycle arrest and embryonic lethality, and not the rampant cell proliferation characteristic of tumours bearing the same mutations.

Genome Stability 1

Following up on our finding that 53BP1 inactivation reverses the cell cycle arrest induced by BRCA1, but not BRCA2 inactivation (Bouwman et al., Nat. Struct. Mol. Biol. 2010), we searched for mutations that can circumvent the proliferative arrest in cells carrying BRCA2 gene deletion. We thus identified ARF as a barrier to uncontrolled proliferation and tumorigenesis onset upon loss of BRCA2 function (Carlos, Escandell et al., Nat. Commun. 2013).

Conversely, using a genetic screen for synthetic lethal interactions with BRCA2 deletion, we discovered that ERK1 (as well as other enzymes of the MAPK pathway) is required to sustain viability of Brca2-deleted cells, regardless of their p53 status (Carlos, Escandell et al., Nat. Commun. 2013). Following up on this, we characterized a novel, highly-selective and potent inhibitor of ERK1/2 kinases released by Merck and demonstrated its in vivo prolonged on-target activity and exceptional specificity in killing BRCA2-deficient cells (Chaikuad et al., Nat. Chem. Biol. 2014).

We have demonstrated that the tumour suppressors BRCA1 and BRCA2 are required for the replication of genomic regions with G quadruplex-forming potential, including telomeres, where they can suppress the genomic instability stemming from inefficient replication of these sites. Indeed, drugs that stabilise G quadruplex structures are particularly toxic to BRCA1/2-deficient cells, highlighting their therapeutic potential in targeting BRCA-deficiency (Zimmer et al., Mol. Cell 2016).

Genome Stability 2

More recently, my group identified a novel synthetically lethal interaction between BRCA2 and FANCD2 gene deletions. Mechanistically, FANCD2 acts to limit constitutive replication stress in BRCA2-deficient cells, which impacts on cell survival and the response to olaparib treatment (Michl, Zimmer et al., Nat. Struct. Mol. Biol 2016).

My laboratory has developed systematic and comprehensive approaches that enabled identification of compounds with specific activity against BRCA1/2-deficient cells, including those that have acquired chemotherapy resistance. Our current work is focused on understanding the mechanism of action of these compounds at cellular level, as well as on their initial validation in pre-clinical settings (xenograft models). We are assessing the efficacy of these drugs in models for chemotherapy resistance or as enhancers of the radiation sensitivity intrinsic to BRCA1/2-deficient cells/tumours.

Genome Stability 3This body of work is deeply relevant to the search for treatments that would selectively kill tumour cells whose capacity for homologous recombination-mediated repair has been compromised and it has, in the longer term, a realistic chance of helping cancer prevention and treatment.

Related research themes