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A catalogue of molecular aberrations that cause ovarian cancer is critical for developing and deploying therapies that will improve patients' lives. The Cancer Genome Atlas project has analysed messenger RNA expression, microRNA expression, promoter methylation and DNA copy number in 489 high-grade serous ovarian adenocarcinomas and the DNA sequences of exons from coding genes in 316 of these tumours. Here we report that high-grade serous ovarian cancer is characterized by TP53 mutations in almost all tumours (96%); low prevalence but statistically recurrent somatic mutations in nine further genes including NF1, BRCA1, BRCA2, RB1 and CDK12; 113 significant focal DNA copy number aberrations; and promoter methylation events involving 168 genes. Analyses delineated four ovarian cancer transcriptional subtypes, three microRNA subtypes, four promoter methylation subtypes and a transcriptional signature associated with survival duration, and shed new light on the impact that tumours with BRCA1/2 (BRCA1 or BRCA2) and CCNE1 aberrations have on survival. Pathway analyses suggested that homologous recombination is defective in about half of the tumours analysed, and that NOTCH and FOXM1 signalling are involved in serous ovarian cancer pathophysiology.

Nearly a quarter century ago, Hanahan and Weinberg conceived six unifying principles explaining how normal cells transform into malignant tumors. Their provisional set of biological capabilities acquired during tumor development-cancer hallmarks-would evolve to 14 tenets as knowledge of cancer genomes, molecular mechanisms, and the tumor microenvironment expanded, most recently adding four emerging enabling characteristics: phenotypic plasticity, epigenetic reprogramming, polymorphic microbiomes, and senescent cells. AKT kinases are critical signaling molecules that regulate cellular physiology upon receptor tyrosine kinases and PI3K activation. The complex branching of the AKT signaling network involves several critical downstream nodes that significantly magnify its functional impact, such that nearly every organ system and cell in the body may be affected by AKT activity. Conversely, tumor-intrinsic dysregulation of AKT can have numerous adverse cellular and pathologic ramifications, particularly in oncogenesis, as multiple tumor suppressors and oncogenic proteins regulate AKT signaling. Herein, we review the mounting evidence implicating the AKT pathway in the aggregate of currently recognized hallmarks of cancer underlying the complexities of human malignant diseases. The challenges, recent successes, and likely areas for exciting future advances in targeting this complex pathway are also discussed., (©2024 American Association for Cancer Research.)

Background: Patients with clear cell renal cell carcinoma (ccRCC) metastases face poor prognoses, even with adjuvant therapies. Tumor-infiltrating T-cells and macrophages are critical in targeting tumor cells within the renal microenvironment. Beyond VHL mutations, loss-of-function mutations in SWI/SNF complex genes, including PBRM1, BAP1, ARID1A, SETD2, SMARCA4 (BRG1), and SMARCA2 (BRM), have been implicated in ccRCC progression., Design: A tissue microarray of 160 ccRCC cases was analyzed via immunohistochemistry (IHC) for SWI/SNF protein expression and CD4 + /CD8 + T-cell infiltration. Clinical and pathologic features were obtained through electronic medical records. Statistical analyses included one-way ANOVA, two-way ANOVA, Pearson's chi-square and t-tests., Results: Loss of SWI/SNF protein expression was observed in PBRM1 (31 %), ARID1A (51 %), SETD2 (14 %), BRG1 (15 %), BRM (38 %), and BAP1 (40 %). T-cell counts varied significantly with stage: CD4 + counts peaked at Stage 3, while CD8 + counts increased through Stage 4 (p < 0.001). Loss of PBRM1 was more frequent in advanced stages (29.4 %, p < 0.001), while BRM and BRG1 losses were more common in earlier stages (p < 0.001, p = 0.006). ARID1A and BRM losses correlated with reduced CD8 + counts (p = 0.016, p = 0.032) and stage-specific CD4 + variations (p < 0.001, p = 0.042)., Conclusion: Loss of PBRM1, SMARCA2/BRM, and SMARCA4/BRG1 expression is significantly associated with ccRCC progression, with PBRM1 loss prevalent in advanced stages and SMARCA2/BRM and SMARCA4/BRG1 in earlier stages. ARID1A and SMARCA2/BRM losses correlate with reduced CD8 + counts and stage-specific CD4 + infiltration, highlighting their potential as biomarkers for disease progression and immunotherapeutic response., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier GmbH. All rights reserved.)

AKT, or protein kinase B, is a central node of the PI3K signaling pathway that is pivotal for a range of normal cellular physiologies that also underlie several pathological conditions, including inflammatory and autoimmune diseases, overgrowth syndromes, and neoplastic transformation. These pathologies, notably cancer, arise if either the activity of AKT or its positive or negative upstream or downstream regulators or effectors goes unchecked, superimposed on by its intersection with a slew of other pathways. Targeting the PI3K/AKT pathway is, therefore, a prudent countermeasure. AKT inhibitors have been tested in many clinical trials, primarily in combination with other drugs. While some have recently garnered attention for their favorable profile, concern over resistance and off-target effects have continued to hinder their widespread adoption in the clinic, mandating a discussion on alternative modes of targeting. In this review, we discuss isoform-centric targeting that may be more effective and less toxic than traditional pan-AKT inhibitors and its significance for disease prevention and treatment, including immunotherapy. We also touch on the emerging mutant- or allele-selective covalent allosteric AKT inhibitors (CAAIs), as well as indirect, novel AKT-targeting approaches, and end with a briefing on the ongoing quest for more reliable biomarkers predicting sensitivity and response to AKT inhibitors, and their current state of affairs., Competing Interests: Declarations. Ethics approval and consent to participate: Not applicable. Competing interests: The authors declare no potential conflicts of interest related to this work., (© 2024. The Author(s).)

The AKT kinases are critical signaling molecules that regulate cellular physiology upon the activation of tyrosine kinase receptors and phosphatidylinositol 3-kinases (PI3K). AKT kinases govern many cellular processes considered hallmarks of cancer, including cell proliferation and survival, cell size, tumor invasion, metastasis, and angiogenesis. AKT signaling is regulated by multiple tumor suppressors and oncogenic proteins whose loss or activation, respectively, leads to dysregulation of this pathway, thereby contributing to oncogenesis. Herein, we review the enormous body of literature documenting how the AKT pathway becomes hyperactivated in sporadic human tumors and various hereditary cancer syndromes. We also discuss the role of activating mutations of AKT pathway genes in various chimeric overgrowth disorders, including Proteus syndrome, hypoglycemia with hypertrophy, CLOVES and SOLAMEN syndromes, and hemimegalencephaly., (© 2024. The Author(s).)

Immunotherapies have demonstrated limited clinical efficacy in malignant mesothelioma treatment. We conducted multiplex immunofluorescence analyses on tissue microarrays (n = 3) from patients with malignant pleural mesothelioma (MPM, n = 88) and malignant peritoneal mesothelioma (MPeM, n = 25). Our study aimed to elucidate spatial distributions of key immune cell populations and their association with lymphocyte activation gene 3 (LAG3), BRCA1-associated protein 1 (BAP1), neurofibromatosis type 2 (NF2), and methylthioadenosine phosphorylase (MTAP), with MTAP serving as a cyclin-dependent kinase inhibitor 2A/2B (CDKN2A/B) surrogate marker. Additionally, we examined the relationship between the spatial distribution of major immune cell types and prognosis and clinical characteristics of patients with malignant mesothelioma. We observed a higher degree of interaction between immune cells and tumor cells in MPM compared with MPeM. Notably, within MPM tumors, we detected a significantly increased interaction between tumor cells and CD8+ T cells in tumors with low BAP1 expression compared with those with high BAP1 expression. To support the broader research community, we have developed The Human Spatial Atlas of Malignant Mesothelioma, containing hematoxylin and eosin and multiplex immunofluorescence images with corresponding metadata., Significance: Considering the limited therapeutic options available to patients with malignant mesothelioma, there is substantial translational potential in understanding the correlation between the spatial architecture of the malignant mesothelioma tumor immune microenvironment and tumor biology. Our investigation reveals critical cell-cell interactions that may influence the immune response against malignant mesothelioma tumors, potentially contributing to the differential behaviors observed in MPM and MPeM. These findings represent a valuable resource for the malignant mesothelioma cancer research community., (©2024 The Authors; Published by the American Association for Cancer Research.)

Acute myeloid leukemia (AML) is a heterogeneous hematological malignancy associated with various combinations of gene mutations, epigenetic abnormalities, and chromosome rearrangement-related gene fusions. Despite the significant degree of heterogeneity in its pathogenesis, many gene fusions and point mutations are recurrent in AML and have been employed in risk stratification over the last several decades. Gene fusions have long been recognized for understanding tumorigenesis and their proven roles in clinical diagnosis and targeted therapies. Advances in DNA sequencing technologies and computational biology have contributed significantly to the detection of known fusion genes as well as for the discovery of novel ones. Several recurring gene fusions in AML have been linked to prognosis, treatment response, and disease progression. In this report, we present a case with a long history of essential thrombocythemia and hallmark CALR mutation transforming to AML characterized by a previously unreported AKAP9::PDGFRA fusion gene. We propose mechanisms by which this fusion may contribute to the pathogenesis of AML and its potential as a molecular target for tyrosine kinase inhibitors., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Author(s).)

Mesothelioma is an incurable cancer of the mesothelial lining often caused by exposure to asbestos. Asbestos-induced inflammation is a significant contributing factor in the development of mesothelioma, and genetic factors also play a role in the susceptibility to this rapidly progressive and treatment-resistant malignancy. Consequently, novel approaches are urgently needed to treat mesothelioma and prevent or reduce the overall incidence of this fatal disease. In this research perspective, we review the current state of chemoprevention and cancer interception progress in asbestos-induced mesothelioma. We discuss the different preclinical mouse models used for these investigations and the inflammatory factors that may be potential targets for mesothelioma prevention. Preliminary studies with naturally occurring phytochemicals and synthetic agents are reviewed. Results of previous clinical chemoprevention trials in populations exposed to asbestos and considerations regarding future trials are also presented., Competing Interests: CONFLICTS OF INTEREST JRT reports a patent on BAP1 mutation testing and has provided legal consultation regarding the role of genetic alterations in mesothelioma. The other authors have no conflicts to declare.

Asbestos and BAP1 germline mutations are risk factors for malignant mesothelioma (MM). While it is well accepted that amphibole asbestos is carcinogenic, the role of serpentine (chrysotile) asbestos in MM has been debated. To address this controversy, we assessed whether minimal exposure to chrysotile could significantly increase the incidence and rate of MM onset in germline Bap1-mutant mice. With either crocidolite or chrysotile, and at each dose tested, MMs occurred at a significantly higher rate and earlier onset time in Bap1-mutant mice than in wild-type littermates. To explore the role of gene-environment interactions in MMs from Bap1-mutant mice, we investigated proinflammatory and protumorigenic factors and the tumor immune microenvironment (TIME). IHC and immunofluorescence staining showed an increased number of macrophages in granulomatous lesions and MMs. The relative number of CD163-positive (CD163+) M2 macrophages in chrysotile-induced MMs was consistently greater than in crocidolite-induced MMs, suggesting that chrysotile induces a more profound immunosuppressive response that creates favorable conditions for evading immune surveillance. MMs from Bap1-mutant mice showed upregulation of CD39/CD73-adenosine and C-C motif chemokine ligand 2 (Ccl2)/C-C motif chemokine receptor 2 (Ccr2) pathways, which together with upregulation of IL6 and IL10, promoted an immunosuppressive TIME, partly by attracting M2 macrophages. Interrogation of published human MM RNA sequencing (RNA-seq) data implicated these same immunosuppressive pathways and connections with CD163+ M2 macrophages. These findings indicate that increased M2 macrophages, along with upregulated CD39/CD73-adenosine and Ccl2/Ccr2 pathways, contribute to an immunosuppressive TIME in chrysotile-induced MMs of Bap1-mutant mice, suggesting that immunotherapeutic strategies targeting protumorigenic immune pathways could be beneficial in human BAP1 mutation carriers who develop MM., Significance: We show that germline Bap1-mutant mice have enhanced susceptibility to MM upon minimal exposure to chrysotile asbestos, not only amphibole fibers. Chrysotile induced a more profound immune tumor response than crocidolite in Bap1-mutant mice by upregulating CD39/CD73-adenosine and Ccl2/Ccr2 pathways and recruiting more M2 macrophages, which together contributed to an immunosuppressive tumor microenvironment. Interrogation of human MM RNA-seq data revealed interconnected immunosuppressive pathways consistent with our mouse findings., (© 2024 The Authors; Published by the American Association for Cancer Research.)

Homologous recombination (HR)-deficiency induces a dependency on DNA polymerase theta (Polθ/Polq)-mediated end joining, and Polθ inhibitors (Polθi) are in development for cancer therapy. BRCA1 and BRCA2 deficient cells are thought to be synthetic lethal with Polθ, but whether distinct HR gene mutations give rise to equivalent Polθ-dependence, and the events that drive lethality, are unclear. In this study, we utilized mouse models with separate Brca1 functional defects to mechanistically define Brca1-Polθ synthetic lethality. Surprisingly, homozygous Brca1 mutant, Polq -/- cells were viable, but grew slowly and had chromosomal instability. Brca1 mutant cells proficient in DNA end resection were significantly more dependent on Polθ for viability; here, treatment with Polθi elevated RPA foci, which persisted through mitosis. In an isogenic system, BRCA1 null cells were defective, but PALB2 and BRCA2 mutant cells exhibited active resection, and consequently stronger sensitivity to Polθi. Thus, DNA end resection is a critical determinant of Polθi sensitivity in HR-deficient cells, and should be considered when selecting patients for clinical studies., (© 2023. The Author(s).)

Malignant mesothelioma (MM) is an incurable cancer of the serosal lining that is often caused by exposure to asbestos. Therefore, novel agents for the prevention and treatment of this disease are urgently needed. Asbestos induces the release of pro-inflammatory cytokines such as IL-1β and IL-6, which play a role in MM development. IL-6 is a component of the JAK-STAT3 pathway that contributes to inflammation-associated tumorigenesis. Glycoprotein 130 (gp130), the signal transducer of this signaling axis, is an attractive drug target because of its role in promoting neoplasia via the activation of downstream STAT3 signaling. The anticancer drug, SC144, inhibits the interaction of gp130 with the IL-6 receptor (IL6R), effectively blunting signaling from this inflammatory axis. To test whether the inflammation-related release of IL-6 plays a role in the formation of MM, we evaluated the ability of SC144 to inhibit asbestos-induced carcinogenesis in a mouse model. The ability of sulindac and anakinra, an IL6R antagonist/positive control, to inhibit MM formation in this model was tested in parallel. Asbestos-exposed Nf2+/-;Cdkn2a+/- mice treated with SC144, sulindac or anakinra showed significantly prolonged survival compared to asbestos-exposed vehicle-treated mice. STAT3 activity was markedly decreased in MM specimens from SC144-treated mice. Furthermore, SC144 inhibited STAT3 activation by IL-6 in cultured normal mesothelial cells, and in vitro treatment of MM cells with SC144 markedly decreased the expression of STAT3 target genes. The emerging availability of newer, more potent SC144 analogs showing improved pharmacokinetic properties holds promise for future trials, benefitting individuals at high risk of this disease., (© The Author(s) 2022. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Malignant pleural mesothelioma (MPM), an aggressive cancer of the mesothelial cells lining the pleural cavity, lacks effective treatments. Multiple somatic mutations and copy number losses in tumor suppressor genes (TSGs) BAP1 , CDKN2A/B , and NF2 are frequently associated with MPM. The impact of single versus multiple genomic alterations of TSG on MPM biology, the immune tumor microenvironment, clinical outcomes, and treatment responses are unknown. Tumors with genomic alterations in BAP1 alone were associated with a longer overall patient survival rate compared to tumors with CDKN2A/B and/or NF2 alterations with or without BAP1 and formed a distinct immunogenic subtype with altered transcription factor and pathway activity patterns. CDKN2A/B genomic alterations consistently contributed to an adverse clinical outcome. Since the genomic alterations of only BAP1 was associated with the PD-1 therapy response signature and higher LAG3 and VISTA gene expression, it might be a candidate marker for immune checkpoint blockade therapy. Our results on the impact of TSG genotypes on MPM and the correlations between TSG alterations and molecular pathways provide a foundation for developing individualized MPM therapies.

The data presented in this article are companion materials to our manuscript titled "BAP1 maintains HIF-dependent interferon beta induction to suppress tumor growth in clear cell renal cell carcinoma" (Langbein et al., 2022), where we investigated the downstream effects of BAP1 (BRCA1-associated protein 1) expression in clear cell renal cell carcinoma (ccRCC) cell lines and mouse xenograft models. In the manuscript, we showed that BAP1 upregulates STING (stimulator of interferon genes) expression and activity in ccRCC cells, leading to IFN-β transcription and activation of interferon stimulated gene factor 3 (ISGF3), the transcription factor that mediates the effects of type I interferons (IFNs). Here, we suppressed additional components of the type I IFN pathway, including IRF9 (a component of ISGF3), IFNAR1 (the type I IFN receptor), and STING (a stimulator of IFN production) by shRNA to investigate their involvement in BAP1-mediated upregulation of ISGF3 activity. We also inhibited extracellular IFN-β via neutralizing antibody treatment in BAP1-expressing cells to ascertain the role of the secreted cytokine in this pathway. ISGF3 activity was assessed by western blot analysis and qPCR measurement of its transcriptional targets. To examine the relevance of our observations in another model system, we characterized primary kidney cells from WT and Bap1 fl/fl mice by cytokeratin 8 immunohistochemistry and examined the effect of Bap1 knockout on Sting protein expression. Finally, we treated mice bearing BAP1 knockdown xenografted tumors with diABZI, a STING agonist, and measured immune cell recruitment via CD45 immunohistochemistry. These data can serve as a starting point for further investigation on the roles of BAP1 and other tumor suppressor genes in interferon pathway regulation., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2022 The Authors.)

BRCA1-associated protein 1 (BAP1) is a deubiquitinase that is mutated in 10-15% of clear cell renal cell carcinomas (ccRCC). Despite the association between BAP1 loss and poor clinical outcome, the critical tumor suppressor function(s) of BAP1 in ccRCC remains unclear. Previously, we found that hypoxia-inducible factor 2α (HIF2α) and BAP1 activate interferon-stimulated gene factor 3 (ISGF3), a transcription factor activated by type I interferons and a tumor suppressor in ccRCC xenograft models. Here, we aimed to determine the mechanism(s) through which HIF and BAP1 regulate ISGF3. We found that in ccRCC cells, loss of the von Hippel-Lindau tumor suppressor (VHL) activated interferon beta (IFN-β) expression in a HIF2α-dependent manner. IFN-β was required for ISGF3 activation and suppressed the growth of Ren-02 tumors in xenografts. BAP1 enhanced the expression of IFN-β and stimulator of interferon genes (STING), both of which activate ISGF3. Both ISGF3 overexpression and STING agonist treatment increased ISGF3 activity and suppressed BAP1-deficient tumor growth in Ren-02 xenografts. Our results indicate that BAP1 loss reduces type I interferon signaling, and reactivating this pathway may be a novel therapeutic strategy for treating ccRCC., Competing Interests: Declaration of competing interest The authors declare no competing interests., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Although alveolar macrophages play a critical role in malignant transformation of mesothelial cells following asbestos exposure, inflammatory and oxidative processes continue to occur in the mesothelial cells lining the pleura that may contribute to the carcinogenic process. Malignant transformation of mesothelial cells following asbestos exposure occurs over several decades; however, amelioration of DNA damage, inflammation, and cell injury may impede the carcinogenic process. We have shown in an in vitro model of asbestos-induced macrophage activation that synthetic secoisolariciresinol diglucoside (LGM2605), given preventively, reduced inflammatory cascades and oxidative/nitrosative cell damage. Therefore, it was hypothesized that LGM2605 could also be effective in reducing asbestos-induced activation and the damage of pleural mesothelial cells. LGM2605 treatment (50 µM) of huma n pleural mesothelial cells was initiated 4 h prior to exposure to asbestos (crocidolite, 20 µg/cm2). Supernatant and cells were evaluated at 0, 2, 4, and 8 h post asbestos exposure for reactive oxygen species (ROS) generation, DNA damage (oxidized guanine), inflammasome activation (caspase-1 activity) and associated pro-inflammatory cytokine release (IL-1β, IL-18, IL-6, TNFα, and HMGB1), and markers of oxidative stress (malondialdehyde (MDA) and 8-iso-prostaglandin F2a (8-iso-PGF2α). Asbestos induced a time-dependent ROS increase that was significantly (p < 0.0001) reduced (29.4%) by LGM2605 treatment. LGM2605 pretreatment also reduced levels of asbestos-induced DNA damage by 73.6% ± 1.0%. Although levels of inflammasome-activated cytokines, IL-1β and IL-18, reached 29.2 pg/mL ± 0.7 pg/mL and 43.9 pg/mL ± 0.8 pg/mL, respectively, LGM2605 treatment significantly (p < 0.0001) reduced cytokine levels comparable to baseline (non-asbestos exposed) values (3.8 pg/mL ± 0.2 pg/mL and 5.4 pg/mL ± 0.2 pg/mL, respectively). Furthermore, levels of IL-6 and TNFα in asbestos-exposed mesothelial cells were high (289.1 pg/mL ± 2.9 pg/mL and 511.3 pg/mL ± 10.2 pg/mL, respectively), while remaining undetectable with LGM2605 pretreatment. HMGB1 (a key inflammatory mediator and initiator of malignant transformation) release was reduced 75.3% ± 0.4% by LGM2605. Levels of MDA and 8-iso-PGF2α, markers of oxidative cell injury, were significantly (p < 0.001) reduced by 80.5% ± 0.1% and 76.6% ± 0.3%, respectively. LGM2605, given preventively, reduced ROS generation, DNA damage, and inflammasome-activated cytokine release and key inflammatory mediators implicated in asbestos-induced malignant transformation of normal mesothelial cells.

Proteolysis-targeting chimeras (PROTACs) are a promising new class of drugs that selectively degrade cellular proteins of interest. PROTACs that target oncogene products are avidly being explored for cancer therapies, and several are currently in clinical trials. Drug resistance is a substantial challenge in clinical oncology, and resistance to PROTACs has been reported in several cancer cell models. Here, using proteomic analysis, we found intrinsic and acquired resistance mechanisms to PROTACs in cancer cell lines mediated by greater abundance or production of the drug efflux pump MDR1. PROTAC-resistant cells were resensitized to PROTACs by genetic ablation of ABCB1 (which encodes MDR1) or by coadministration of MDR1 inhibitors. In MDR1-overexpressing colorectal cancer cells, degraders targeting either the kinases MEK1/2 or the oncogenic mutant GTPase KRAS G12C synergized with the dual epidermal growth factor receptor (EGFR/ErbB)/MDR1 inhibitor lapatinib. Moreover, compared with single-agent therapies, combining MEK1/2 degraders with lapatinib improved growth inhibition of MDR1-overexpressing KRAS-mutant colorectal cancer xenografts in mice. Together, our findings suggest that concurrent blockade of MDR1 will likely be required with PROTACs to achieve durable protein degradation and therapeutic response in cancer.

Malignant mesothelioma (MMe) is a rare malignancy originating from the linings of the pleural, peritoneal and pericardial cavities. The best-defined risk factor is exposure to carcinogenic mineral fibers (e.g., asbestos). Genomic studies have revealed that the most frequent genetic lesions in human MMe are mutations in tumor suppressor genes. Several genetically engineered mouse models have been generated by introducing the same genetic lesions found in human MMe. However, most of these models require specialized breeding facilities and long-term exposure of mice to asbestos for MMe development. Thus, an alternative model with high tumor penetrance without asbestos is urgently needed. We characterized an orthotopic model using MMe cells derived from Cdkn2a +/- ;Nf2 +/- mice chronically injected with asbestos. These MMe cells were tumorigenic upon intraperitoneal injection. Moreover, MMe cells showed mixed chromosome and microsatellite instability, supporting the notion that genomic instability is relevant in MMe pathogenesis. In addition, microsatellite markers were detectable in the plasma of tumor-bearing mice, indicating a potential use for early cancer detection and monitoring the effects of interventions. This orthotopic model with rapid development of MMe without asbestos exposure represents genomic instability and specific molecular targets for therapeutic or preventive interventions to enable preclinical proof of concept for the intervention in an immunocompetent setting.

Because loss of the NF2 tumor suppressor gene results in p21-activated kinase (Pak) activation, PAK inhibitors hold promise for the treatment of NF2-deficient tumors. To test this possibility, we asked if loss of Pak2, a highly expressed group I PAK member, affects the development of malignant mesothelioma in Nf2;Cdkn2a-deficient (NC) mice and the growth properties of NC mesothelioma cells in culture. In vivo, deletion of Pak2 resulted in a markedly decreased incidence and delayed onset of both pleural and peritoneal malignant mesotheliomas in NC mice. In vitro, Pak2 deletion decreased malignant mesothelioma cell viability, migration, clonogenicity, and spheroid formation. RNA-sequencing analysis demonstrated downregulated expression of Hedgehog and Wnt pathway genes in NC;Pak2-/- mesothelioma cells versus NC;Pak2+/+ mesothelioma cells. Targeting of the Hedgehog signaling component Gli1 or its target gene Myc inhibited cell viability and spheroid formation in NC;P+/+ mesothelioma cells. Kinome profiling uncovered kinase changes indicative of EMT in NC;Pak2-/- mesothelioma cells, suggesting that Pak2-deficient malignant mesotheliomas can adapt by reprogramming their kinome in the absence of Pak activity. The identification of such compensatory pathways offers opportunities for rational combination therapies to circumvent resistance to anti-PAK drugs., Implications: We provide evidence supporting a role for PAK inhibitors in treating NF2-deficient tumors. NF2-deficient tumors lacking Pak2 eventually adapt by kinome reprogramming, presenting opportunities for combination therapies to bypass anti-PAK drug resistance., (©2022 American Association for Cancer Research.)

Microphthalmia-associated transcription factor (MITF/MiT) family is a group of basic helix-loop-helix leucine zipper (bHLH-LZ) transcription factors including TFE3 (TFEA), TFEB, TFEC and MITF. The first renal neoplasms involving MITF family translocation were renal cell carcinomas with chromosome translocations involving ASPL-TFE3/t(X;17)(p11.23;q25) or MALAT1-TFEB/t(6;11)(p21.1;q12), and now it is known as MiT family translocation RCC in 2016 WHO classification. Translocations involving MITF family genes also are found in other tumor types, such as perivascular epithelioid cell neoplasm (PEComa), Alveolar soft part sarcoma (ASPS), epithelioid hemangioendothelioma, ossifying fibromyxoid tumor (OFMT), and clear cell tumor with melanocytic differentiation and ACTIN-MITF translocation. In this review, we summarize the features of different types of neoplasms with MITF family translocations.