RESUMO
Small cell lung cancer (SCLC) is generally regarded as very difficult to treat, mostly due to the development of metastases early in the disease and a quick relapse with resistant disease. SCLC patients initially show a good response to treatment with the DNA damaging agents cisplatin and etoposide. This is, however, quickly followed by the development of resistant disease, which urges the development of novel therapies for this type of cancer. In this study, we set out to compile a comprehensive overview of the vulnerabilities of SCLC. A functional genome-wide screen where all individual genes were knocked out was performed to identify novel vulnerabilities of SCLC. By analysis of the knockouts that were lethal to these cancer cells, we identified several processes to be synthetic vulnerabilities in SCLC. We were able to validate the vulnerability to inhibition of the replication stress response machinery by use of Chk1 and ATR inhibitors. Strikingly, SCLC cells were more sensitive to these inhibitors than nontransformed cells. In addition, these inhibitors work synergistically with either etoposide and cisplatin, where the interaction is largest with the latter. ATR inhibition by VE-822 treatment in combination with cisplatin also outperforms the combination of cisplatin with etoposide in vivo Altogether, our study uncovered a critical dependence of SCLC on the replication stress response and urges the validation of ATR inhibitors in combination with cisplatin in a clinical setting.
Assuntos
Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Cisplatino/uso terapêutico , Isoxazóis/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Pirazinas/uso terapêutico , Carcinoma de Pequenas Células do Pulmão/tratamento farmacológico , Células A549 , Animais , Antineoplásicos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Proteínas Mutadas de Ataxia Telangiectasia/antagonistas & inibidores , Proteína 9 Associada à CRISPR/genética , Sobrevivência Celular/efeitos dos fármacos , Quinase 1 do Ponto de Checagem/antagonistas & inibidores , Cisplatino/administração & dosagem , Dano ao DNA/efeitos dos fármacos , Sinergismo Farmacológico , Etoposídeo/administração & dosagem , Etoposídeo/uso terapêutico , Humanos , Isoxazóis/administração & dosagem , Isoxazóis/farmacologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/farmacologia , Pirazinas/administração & dosagem , Pirazinas/farmacologia , Carga Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Chromosomal rearrangements are mutations contributing to both within and between species variation; however their contribution to fitness is yet to be measured. Here we show that chromosomal rearrangements are pervasive in natural isolates of Schizosaccharomyces pombe and contribute to reproductive isolation. To determine the fitness effects of chromosome structure, we constructed two inversions and eight translocations without changing the coding sequence. We show that chromosomal rearrangements contribute to both reproductive success in meiosis and growth rate in mitosis with a strong genotype by environment interaction. These changes are accompanied by alterations in gene expression. Strikingly, we find several examples leading to antagonistic pleiotropy. Even though chromosomal rearrangements may have a deleterious effect during sexual reproduction, some compensate with a strong growth advantage in mitosis. Our results constitute the first quantification of fitness effects caused by de novo mutations that result in chromosomal rearrangement variation and suggest a mechanism for their maintenance in natural populations.