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Effect of prolonged RANKL-blockade with OPG-Fc in RANK-overexpressing luminal breast cancer
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O cancro de mama (CM) metastático tem uma sobrevivência a 5 anos de apenas 27%, sendo responsável por 685.000 mortes todos os anos, 1800 em Portugal. Recentemente, os inibidores das cinases dependentes das ciclinas 4 e 6 (inibidores de CDK4/6) foram aprovados para o tratamento de CM metastático recetor de estrogénios positivo (RE+) HER2-negativo (HER2-), em combinação com a hormonoterapia (HT). Entre os doentes refratários ou resistentes, ainda não existem biomarcadores preditivos de resposta. A cascata de sinalização do recetor ativador do fator nuclear kB (RANK) desempenha um papel chave em todas as fases do CM. Recentemente, o nosso grupo demonstrou que células de CM RE+/HER2- com sobre-expressão do RANK (RANK OE) apresentam um fenótipo estaminal e mesenquimatoso, com uma menor taxa de proliferação e menor sensibilidade à quimioterapia e HT. Posteriormente, descobrimos que as células RANK OE in vitro são resistentes aos inibidores de CDK4/6. Adicionalmente, observámos in vivo que o bloqueio da via RANK com osteoprotegerina-Fc (OPG-Fc), um recetor decoy solúvel do RANK ligando (RANKL), reestabelece a sensibilidade à HT nas células RANK OE, e que a OPG-Fc per se induziu uma maior taxa de proliferação das células RANK OE que se traduziu num maior crescimento dos xenotransplantes, intrinsecamente quiescentes in vivo. Assim, colocamos a hipótese que, no contexto clínico, não só a sobre-expressão de RANK poderá ser preditiva da resistência aos inibidores de CDK4/6, como a inibição da via RANK poderá sensibilizar o CM Luminal a esta terapia. Uma vez que a exposição curta a OPG-Fc in vitro não se traduz em alterações significativas na proliferação celular, embora sensibilize as células RANK OE à terapia, este projeto teve como objetivo avaliar in vitro o efeito sobre a taxa de proliferação e a sensibilidade à terapia da exposição contínua e prolongada a OPG-Fc em células de CM RE+/HER2, com e sem sobre-expressão de RANK. Os nossos resultados demonstram que o bloqueio prolongado do RANKL com OPG-Fc aumenta a proliferação das células RANK OE; e, ao desbloquear a proliferação celular, reestabelece a sensibilidade à terapêutica com HT, inibidores de CDK4/6 ou a sua combinação. Estes resultados abrem caminho para o estudo da eficácia da inibição da via RANK em CM Luminal metastático.
Advanced breast cancer (BC) has a 5-year relative survival rate of only 27% and kills over 685.000 women each year, 1800 in Portugal. Current treatment of estrogen receptor (ER)-positive (ER+)/HER2-negative advanced BC includes the recently approved cyclindependent kinase 4 and 6 (CDK4/6) inhibitors and endocrine therapy (ET). While a significant percentage of the patients develop clinical resistance, predictive biomarkers of CDK4/6 inhibitors’ efficacy remain undefined. The receptor activator of nuclear factor kB (RANK) signaling pathway plays a crucial role in all stages of BC. Recently, our group found that RANK overexpressing (RANK OE) ER+/HER2- BC cells showed a staminal and mesenchymal phenotype, with decreased proliferation rate and reduced susceptibility to chemotherapy and ET. These results supported the effectiveness of RANK pathway inhibition to improve ER+HER2- BC outcomes. Since then, we discovered that RANK OE cells are resistant to CDK4/6 inhibitors in vitro. Additionally, short exposure to osteoprotegerin-Fc (OPG-Fc) in vitro did not translate into differences in proliferation but was able to re-establish sensitivity to therapy in RANK OE cells, with or without ET. In vivo, blockage of RANK-pathway with OPG-Fc restored sensitivity to therapy in RANK OE ER+ BC cells and unlocked the RANK-dependent restrained growth of RANK OE cells. Therefore, we hypothesize that, in the clinical setting, RANK overexpression in ER+/HER2- BC may predict resistance to CDK4/6 inhibitors and RANK inhibition may sensitize BC to therapy. Thus, this project aims to evaluate in vitro the effects on proliferation and treatment sensitivity of prolonged RANKL blockade with OPG-Fc in Luminal BC, with or without RANK OE. Our results demonstrate that prolonged RANKL blockade with OPG-Fc increases the proliferation of RANK-high Luminal BC cells; and restores sensitivity to therapy -HT, CDK4/6 inhibitors, or its combination-, by unlocking cell proliferation. These results pave the way to study the clinical effectiveness of RANK pathway inhibition in Luminal BC.
Advanced breast cancer (BC) has a 5-year relative survival rate of only 27% and kills over 685.000 women each year, 1800 in Portugal. Current treatment of estrogen receptor (ER)-positive (ER+)/HER2-negative advanced BC includes the recently approved cyclindependent kinase 4 and 6 (CDK4/6) inhibitors and endocrine therapy (ET). While a significant percentage of the patients develop clinical resistance, predictive biomarkers of CDK4/6 inhibitors’ efficacy remain undefined. The receptor activator of nuclear factor kB (RANK) signaling pathway plays a crucial role in all stages of BC. Recently, our group found that RANK overexpressing (RANK OE) ER+/HER2- BC cells showed a staminal and mesenchymal phenotype, with decreased proliferation rate and reduced susceptibility to chemotherapy and ET. These results supported the effectiveness of RANK pathway inhibition to improve ER+HER2- BC outcomes. Since then, we discovered that RANK OE cells are resistant to CDK4/6 inhibitors in vitro. Additionally, short exposure to osteoprotegerin-Fc (OPG-Fc) in vitro did not translate into differences in proliferation but was able to re-establish sensitivity to therapy in RANK OE cells, with or without ET. In vivo, blockage of RANK-pathway with OPG-Fc restored sensitivity to therapy in RANK OE ER+ BC cells and unlocked the RANK-dependent restrained growth of RANK OE cells. Therefore, we hypothesize that, in the clinical setting, RANK overexpression in ER+/HER2- BC may predict resistance to CDK4/6 inhibitors and RANK inhibition may sensitize BC to therapy. Thus, this project aims to evaluate in vitro the effects on proliferation and treatment sensitivity of prolonged RANKL blockade with OPG-Fc in Luminal BC, with or without RANK OE. Our results demonstrate that prolonged RANKL blockade with OPG-Fc increases the proliferation of RANK-high Luminal BC cells; and restores sensitivity to therapy -HT, CDK4/6 inhibitors, or its combination-, by unlocking cell proliferation. These results pave the way to study the clinical effectiveness of RANK pathway inhibition in Luminal BC.
Descrição
Trabalho Final do Curso de Mestrado Integrado em Medicina, Faculdade de Medicina, Universidade de Lisboa, 2021
Palavras-chave
Cancro de mama Receptor ativador do fator nuclear kB (RANK) Inibidores de cinases dependentes de ciclinas 4/6 Receptor activador do fator nuclear kB-ligand (RANKL) Oncobiologia