Liver cancer remains difficult to treat, owing to a paucity of drugs that target critical dependencies
; broad-spectrum kinase inhibitors such as sorafenib provide only a modest benefit to patients ...with hepatocellular carcinoma
. The induction of senescence may represent a strategy for the treatment of cancer, especially when combined with a second drug that selectively eliminates senescent cancer cells (senolysis)
. Here, using a kinome-focused genetic screen, we show that pharmacological inhibition of the DNA-replication kinase CDC7 induces senescence selectively in liver cancer cells with mutations in TP53. A follow-up chemical screen identified the antidepressant sertraline as an agent that kills hepatocellular carcinoma cells that have been rendered senescent by inhibition of CDC7. Sertraline suppressed mTOR signalling, and selective drugs that target this pathway were highly effective in causing the apoptotic cell death of hepatocellular carcinoma cells treated with a CDC7 inhibitor. The feedback reactivation of mTOR signalling after its inhibition
is blocked in cells that have been treated with a CDC7 inhibitor, which leads to the sustained inhibition of mTOR and cell death. Using multiple in vivo mouse models of liver cancer, we show that treatment with combined inhibition of of CDC7 and mTOR results in a marked reduction of tumour growth. Our data indicate that exploiting an induced vulnerability could be an effective treatment for liver cancer.
Ubiquitous expression of a resident K-Ras ᴳ¹²ⱽ oncogene in adult mice revealed that most tissues are resistant to K-Ras oncogenic signals. Indeed, K-Ras ᴳ¹²ⱽ expression only induced overt tumors in ...lungs. To identify these transformation-permissive cells, we induced K-Ras ᴳ¹²ⱽ expression in a very limited number of adult lung cells (0.2%) and monitored their fate by X-Gal staining, a surrogate marker coexpressed with the K-Ras ᴳ¹²ⱽ oncoprotein. Four weeks later, 30% of these cells had proliferated to form small clusters. However, only SPC ⁺ alveolar type II (ATII) cells were able to form hyperplastic lesions, some of which progressed to adenomas and adenocarcinomas. In contrast, induction of K-Ras ᴳ¹²ⱽ expression in lung cells by intratracheal infection with adenoviral-Cre particles generated hyperplasias in all regions except the proximal airways. Bronchiolar and bronchioalveolar duct junction hyperplasias were primarily made of CC10 ⁺ Clara cells. Some of them progressed to form benign adenomas. However, only alveolar hyperplasias, exclusively made up of SPC ⁺ ATII cells, progressed to yield malignant adenocarcinomas. Adenoviral infection induced inflammatory infiltrates primarily made of T and B cells. This inflammatory response was essential for the development of K-Ras ᴳ¹²ⱽ–driven bronchiolar hyperplasias and adenomas, but not for the generation of SPC ⁺ ATII lesions. Finally, activation of K-Ras ᴳ¹²ⱽ during embryonic development under the control of a Sca1 promoter yielded CC10 ⁺, but not SPC ⁺, hyperplasias, and adenomas. These results, taken together, illustrate that different types of lung cells can generate benign lesions in response to K-Ras oncogenic signals. However, in adult mice, only SPC ⁺ ATII cells were able to yield malignant adenocarcinomas.
Senescence is a proliferation arrest that can result from a variety of stresses. Cancer cells can also undergo senescence, but the stresses that provoke cancer cells to undergo senescence are ...unclear. Here, we use both functional genetic and compound screens in cancer cells harboring a reporter that is activated during senescence to find targets that induce senescence. We show that suppression of the SWI/SNF component SMARCB1 induces senescence in melanoma through strong activation of the MAP kinase pathway. From the compound screen, we identified multiple aurora kinase inhibitors as potent inducers of senescence in RAS mutant lung cancer. Senescent melanoma and lung cancer cells acquire sensitivity to the BCL2 family inhibitor ABT263. We propose a one-two punch approach for the treatment of cancer in which a drug is first used to induce senescence in cancer cells and a second drug is then used to kill senescent cancer cells.
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•CRISPR and chemical screens identify senescence inducers in cancer cells•SMARCB1 knockout induces senescence in melanoma•Aurora kinase inhibition induces senescence in multiple cancer types•Senescent cancer cells become vulnerable to killing by ABT263
Wang et al. find that CRISPR-mediated genetic screens and chemical screens serve as two types of high-throughput methods to identify senescence inducers in cancer cells. They also show that senescent cancer cells can be killed selectively by the BCL2-family inhibitor ABT263, providing a potential sequential drug treatment strategy for cancer.
Hirt et al.1 report an automated, high-throughput drug screening platform for organoid cultures to enable repurposing of previously approved drugs for pancreatic cancers harboring specific genetic ...alterations. The pancreatic cancer organoid biobank also represents a valuable tool to uncover new drug-gene interactions in pancreatic tumors.
Hirt et al. report an automated, high-throughput drug screening platform for organoid cultures to enable repurposing of previously approved drugs for pancreatic cancers harboring specific genetic alterations. The pancreatic cancer organoid biobank also represents a valuable tool to uncover new drug-gene interactions in pancreatic tumors.
Liver cancer is the fourth most common cause of cancer‐related death worldwide, with hepatocellular carcinoma (HCC) being the main primary malignancy affecting the liver. Unfortunately, there are ...still limited therapeutic options for HCC, and even the latest advances have only increased the overall survival modestly. Thus, new treatment strategies and rational drug combinations are urgently needed. Reactivation of receptor tyrosine kinases (RTK) has been described as a mechanism of intrinsic resistance to targeted therapies in a variety of cancers, including inhibitors of mTOR. The design of rational combination therapies to overcome this type of resistance is complicated by the notion that multiple RTK can be upregulated during the acquisition of resistance. SHP2, encoded by the gene PTPN11, acts downstream of virtually all RTK, and has proven to be a good target for small molecule inhibitors. Here, we report activation of multiple RTK upon mTOR inhibition in HCC which, through SHP2, leads to reactivation of the mTOR pathway. We show that co‐inhibition of both mTOR and SHP2 is highly synergistic in vitro by triggering apoptosis. More importantly, the combination is well‐tolerated and outperforms the monotherapies in impairing tumor growth in multiple HCC mouse models. Our findings suggest a novel rational combination therapy for the treatment of HCC.
We show that, upon mTOR inhibition with AZD8055, there is upregulation of several receptor tyrosine kinases. As consequence, SHP2 signals through the mTOR pathway. Hence, dual blockade of SHP2 and mTOR can effectively suppress the mTOR pathway and drive anti‐cancer response, both in vitro and in vivo, in several hepatocellular carcinoma models.
Mutation-selective KRAS inhibitors are revolutionizing the treatment of RAS-mutant tumors but cannot achieve durable effects alone. Kemp and colleagues1 recently showed how the KRAS-G12D-specific ...inhibitor MRTX1133, while impairing cancer proliferation, stimulates T cell infiltration, which is crucial for sustained disease control.
Mutation-selective KRAS inhibitors are revolutionizing the treatment of RAS-mutant tumors but cannot achieve durable effects alone. Kemp and colleagues1 recently showed how the KRAS-G12D-specific inhibitor MRTX1133, while impairing cancer proliferation, stimulates T cell infiltration, which is crucial for sustained disease control.
Este artigo busca analisar, através da obra de Simone de Beauvoir: O segundo sexo, o espaço da mulher na sociedade. A obra foi estudada na disciplina de Filosofia Contemporânea do curso de ...Licenciatura em Filosofia pela Universidade do Estado de Mato Grosso – UNEMAT. Tem por objetivo expor as dificuldades enfrentadas pelas mulheres no decorrer da história até a contemporaneidade, com a intenção de destacar a luta e sua coragem frente a uma sociedade construída pelos homens e para os homens, destacando o nascimento de muitos direitos conquistados pelo sexo feminino. Sendo assim, a pesquisa aborda o movimento feminista e a sua importância diante de todo processo de busca por respeito pelo segundo sexo, expondo um olhar sobre o que significava ser mulher, sob a ótica de como a mulher era vista e o que esperavam dela, comparando-se com os dias atuais. Usando Simone de Beauvoir como referência de personalidade feminina, como alguém que alcançou um espaço valioso para todas as mulheres.
The Kirsten rat sarcoma viral oncogene homologue
is among the most commonly mutated oncogenes in human cancers, thus representing an attractive target for precision oncology. The approval for ...clinical use of the first selective inhibitors of G12C mutant KRAS therefore holds great promise for cancer treatment. However, despite initial encouraging clinical results, the overall survival benefit that patients experience following treatment with these inhibitors has been disappointing to date, pointing toward the need to develop more powerful combination therapies. Here, we show that responsiveness to KRAS
and pan-RAS inhibitors in
-mutant lung and colon cancer cells is limited by feedback activation of the parallel MAP2K4-JNK-JUN pathway. Activation of this pathway leads to elevated expression of receptor tyrosine kinases that reactivate KRAS and its downstream effectors in the presence of drug. We find that the combination of sotorasib, a drug targeting KRAS
, and the MAP2K4 inhibitor HRX-0233 prevents this feedback activation and is highly synergistic in a panel of
-mutant lung and colon cancer cells. Moreover, combining HRX-0233 and sotorasib is well-tolerated and resulted in durable tumor shrinkage in mouse xenografts of human lung cancer cells, suggesting a therapeutic strategy for KRAS-driven cancers.
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