Exploring mechanisms of resistance against ER+ and BRCA1 breast cancer therapies

• Various research lines led by VHIO aim at better deciphering how tumor cells acquire resistance to anticancer agents including palbociclib and treatments inducing DNA damage

• The expression of partially functional BRCA1 proteins can explain the poor response to BRCA1 breast and ovarian cancer therapies

• The combination of a CDK4/6 inhibitor, hormone therapy and PI3K pathway inhibitors puts the brakes on resistance in ER-positive breast cancer patients

VHIO´s Experimental Therapies Group, led by Violeta Serra, studies the mechanisms by which breast tumors acquire resistance to therapy. Three studies have recently been published reporting on the group´s latest discovery into ER-positive and BRCA1 breast cancers, carried out in collaboration with VHIO´s Breast Cancer and High Risk & Cancer Prevention groups, headed by Cristina Saura and Judith Balmaña respectively.

In two of these latest papers, VHIO researchers, using patient-derived xenograft models (PDX) to predict response to therapy, evidenced the development of resistance to treatments inducing DNA damage in patients with two of the most common BRCA1 mutations.

The BRCA1 protein is implicated in several cellular processes including DNA damage repair, transcriptional regulation, and cell cycle control. Its role in DNA damage repair is essential for tumor suppressor function. Tumors with alterations in this gene are therefore highly sensitive to therapies inducing DNA damage as well as PARP inhibitors. However, these latest findings have revealed that some tumors with BRCA1 mutations can re-express a partially functional protein, leading to resistance to targeted therapies in this population. Upon confirming these results in humans, through tests facilitating the measurement of protein activity, researchers may be able to better predict response to this type of therapy.

In another study, published in Cancer Research, carried out in partnership with Nicholas C. Turner, a team leader at The Institute of Cancer Research and consultant at The Royal Marsden, London, UK, Violeta´s group has also explored mechanisms of resistance of ER-positive breast cancers to CDK4/6 inhibitors including palbociclib. These preclinical findings, selected by the American Society of Clinical Oncology (ASCO) for coverage in The ASCO Post, suggest that different combinations of therapeutics might prevent and overcome the acquisition of resistance to these anticancer agents.

CDK4/6 inhibitors are novel agents for the treatment of ER-positive metastatic breast cancer. While these new anti-cancer therapies have demonstrated their efficacy, many of these tumors will ultimately develop resistance. “There is consequently a critical need to identify how these cancer cells acquire resistance. Potential combinations of anticancer agents capable of delaying the onset of resistance or eradicating it upon occurrence need to be identified, tried and tested,” observes Violeta.

Upon screening 3,530 compounds for their capacity to synergize with the CDK4/6 inhibitor in blocking the growth of ER+ cancer cells in vitro, the researchers found that many inhibited the PI3K pathway. Turner and Violeta´s group discovered that combining a CDK4/6 inhibitor or PI3K pathway inhibitor with hormone therapy led to significant tumor regression in in vitro cancer cultures and in in vivo patient-derived models. “Other analyses have identified different mechanisms by which tumor cells develop resistance to CDK4/6 inhibitors,” continues Serra. This therapeutic pairing is already being tested in a phase Ib clinical trial.

The next step will involve studying ER-positive breast cancer patient samples that have developed resistance in order to establish whether the mechanism that the research team identified in preclinical studies occurs at clinical level. If so, a test will need to be developed that can distinguish between the different types of resistance, thereby enabling selection of the most appropriate treatment plan for each individual patient.


For more information please contact: Amanda Wren, Director of Communications, Vall d´Hebron Institute of Oncology (VHIO), Tel: +34 695 207 886, Email: awren@vhio.net.


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