Senolytics: from pharmacological inhibitors to immunotherapies, a promising future for patients' treatment.

The involvement of cellular senescence in the initiation and propagation of diseases is clearly characterized, making the elimination of senescent cells essential to treat age-related diseases. The development of senolytic drugs demonstrated that targeting these cells limits the deterioration of patients' condition, by inducing apoptosis. Nevertheless, the first generations of senolytics which has been developed displayed their activities through specific mechanisms and demonstrated several limitations during clinical development. However, the rational to eliminate senescent cells remains evident, with the necessity to develop specific therapies in a context of diseases and tissues. The evolutions in the field of drug discovery open the way to a new generation of senolytic therapies, such as immunological approaches (CAR-T cells, Antibody-Drug Conjugated or vaccines), which require preliminary steps of research to identify markers specifically expressed on senescent cells, demonstrating promising specific effects. Currently, the preclinical development of these strategies appears more challenging to avoid strong side effects, but the expected results are commensurate with patients' hopes for treatments. In this review, we highlight the fact that the classical senolytic approach based on drug repurposing display limited efficacy and probably reached its limits in term of clinical development. The recent development of more complex therapies and the extension of interest in the domain of senescence in different fields of research allow to extend the possibility to discover powerful therapies. The future of age-related diseases treatment is linked to the development of new approaches based on cell therapy or immunotherapy to offer the best treatment for patients.

Targeting ribosome biogenesis reinforces ERK-dependent senescence in pancreatic cancer.

Pancreatic adenocarcinomas (PDAC) often possess mutations in K-Ras that stimulate the ERK pathway. Aberrantly high ERK activation triggers oncogene-induced senescence, which halts tumor progression. Here we report that low-grade pancreatic intraepithelial neoplasia displays very high levels of phospho-ERK consistent with a senescence response. However, advanced lesions that have circumvented the senescence barrier exhibit lower phospho-ERK levels. Restoring ERK hyperactivation in PDAC using activated RAF leads to ERK-dependent growth arrest with senescence biomarkers. ERK-dependent senescence in PDAC was characterized by a nucleolar stress response including a selective depletion of nucleolar phosphoproteins and intranucleolar foci containing RNA polymerase I designated as senescence-associated nucleolar foci (SANF). Accordingly, combining ribosome biogenesis inhibitors with ERK hyperactivation reinforced the senescence response in PDAC cells. Notably, comparable mechanisms were observed upon treatment with the platinum-based chemotherapy regimen FOLFIRINOX, currently a first-line treatment option for PDAC. We thus suggest that drugs targeting ribosome biogenesis can improve the senescence anticancer response in pancreatic cancer.

The PLA2R1-JAK2 pathway upregulates ERRα and its mitochondrial program to exert tumor-suppressive action.

Little is known about the biological role of the phospholipase A2 receptor (PLA2R1) transmembrane protein. In recent years, PLA2R1 has been shown to have an important role in regulating tumor-suppressive responses via JAK2 activation, but the underlying mechanisms are largely undeciphered. In this study, we observed that PLA2R1 increases the mitochondrial content, judged by increased levels of numerous mitochondrial proteins, of the mitochondrial structural component cardiolipin, of the mitochondrial DNA content, and of the mitochondrial DNA replication and transcription factor TFAM. This effect of PLA2R1 relies on a transcriptional program controlled by the estrogen-related receptor alpha1 (ERRα) mitochondrial master regulator. Expression of ERRα and of its nucleus-encoded mitochondrial targets is upregulated upon PLA2R1 ectopic expression, and this effect is mediated by JAK2. Conversely, downregulation of PLA2R1 decreases the level of ERRα and of its nucleus-encoded mitochondrial targets. Finally, blocking the ERRα-controlled mitochondrial program largely inhibits the PLA2R1-induced tumor-suppressive response. Together, our data document ERRα and its mitochondrial program as downstream effectors of the PLA2R1-JAK2 pathway leading to oncosuppression.

Multidrug resistance protein 3 loss promotes tumor formation by inducing senescence escape.

Oncogenic-stress-induced senescence (OIS) is a stress response allowing normal cells, when receiving oncogenic signals, to stably arrest their proliferation. OIS thus acts to prevent aberrant cell proliferation and tumor formation. To identify novel tumor suppressive pathways, we have recently completed a loss-of-function genetic screen to identify novel genes promoting escape from OIS and thus, potentially, tumor formation when their functions are lost. Using this approach, we unexpectedly found that loss of function of the multidrug resistance protein 3 (MRP3 or ABCC3) promotes escape from OIS in human epithelial cells. Importantly, ABCC3 expression is reduced in human skin tumors, and ABCC3-knockout mice display increased sensitivity to RAS-induced skin carcinogenesis, concomitantly with decreased OIS. ABCC3 participates in resistance to chemotherapy via its transporter activity. Our data show that this transporter activity is involved in ABCC3-induced senescence, demonstrating that this protein has a complex role in cancer, since its loss of function may promote escape from OIS and tumor formation whereas its gain of function promotes resistance to chemotherapy.

Lysyl oxidase activity regulates oncogenic stress response and tumorigenesis.

Cellular senescence, a stable proliferation arrest, is induced in response to various stresses. Oncogenic stress-induced senescence (OIS) results in blocked proliferation and constitutes a fail-safe program counteracting tumorigenesis. The events that enable a tumor in a benign senescent state to escape from OIS and become malignant are largely unknown. We show that lysyl oxidase activity contributes to the decision to maintain senescence. Indeed, in human epithelial cell the constitutive expression of the LOX or LOXL2 protein favored OIS escape, whereas inhibition of lysyl oxidase activity was found to stabilize OIS. The relevance of these in vitro observations is supported by in vivo findings: in a transgenic mouse model of aggressive pancreatic ductal adenocarcinoma (PDAC), increasing lysyl oxidase activity accelerates senescence escape, whereas inhibition of lysyl oxidase activity was found to stabilize senescence, delay tumorigenesis, and increase survival. Mechanistically, we show that lysyl oxidase activity favors the escape of senescence by regulating the focal-adhesion kinase. Altogether, our results demonstrate that lysyl oxidase activity participates in primary tumor growth by directly impacting the senescence stability.