A Mesenchymal Tumor Cell State Confers Increased Dependency on the BCL-XL Antiapoptotic Protein in Kidney Cancer

Grubb, Treg; Maganti, Smruthi; Krill-Burger, John M.; Fraser, Colin; Stransky, Laura; Radivoyevitch, Tomas; Sarosiek, Kristopher A.; Vázquez, Francisca; Kaelin, William G.; Chakraborty, Abhishek A.

doi:10.1158/1078-0432.ccr-22-0669

Cited by 9 publications

(5 citation statements)

References 49 publications

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“…GBN2, a member of the guanine nucleotide-binding proteins family, has been reported that the decrease of its expression reduced tumor cell proliferation (Zhang et al, 2019). A recent study identified a strong dependency on BCL2L1, which encodes the BCL-XL anti-apoptotic protein, in a subset of kidney cancer cells (Grubb et al, 2022). This biological interpretability revealed established and novel molecular features contributing to kidney cancer.…”

Section: Resultsmentioning

confidence: 93%

Deep Biological Pathway Informed Pathology-Genomic Multimodal Survival Prediction

Qiu¹,

Khormali²,

Li³

2023

Preprint

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The integration of multi-modal data, such as pathological images and genomic data, is essential for understanding cancer heterogeneity and complexity for personalized treatments, as well as for enhancing survival predictions. Despite the progress made in integrating pathology and genomic data, most existing methods cannot mine the complex inter-modality relations thoroughly. Additionally, identifying explainable features from these models that govern preclinical discovery and clinical prediction is crucial for cancer diagnosis, prognosis, and therapeutic response studies. We propose PONET-a novel biological pathway informed pathology-genomic deep model that integrates pathological images and genomic data not only to improve survival prediction but also to identify genes and pathways that cause different survival rates in patients. Empirical results on six of The Cancer Genome Atlas (TCGA) datasets show that our proposed method achieves superior predictive performance and reveals meaningful biological interpretations. The proposed method establishes insight into how to train biologically informed deep networks on multimodal biomedical data which will have general applicability for understanding diseases and predicting response and resistance to treatment.

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Section: Resultsmentioning

confidence: 93%

Deep Biological Pathway Informed Pathology-Genomic Multimodal Survival Prediction

Qiu¹,

Khormali²,

Li³

2023

Preprint

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“…Previous studies have similarly shown that upregulation of proapoptotic gene signatures primes cancer cells for apoptosis and could serve as a biomarker for increased sensitivity to inhibition of Bcl-2 family members (63)(64)(65)(66). A recent report further demonstrated that a subset of ccRCC characterized by a mesenchymal transcriptional profile is highly dependent on BCLxL, another Bcl-2 family member (67). Interestingly, MCL1 expression was lower in PBRM1 loss ccRCC compared to WT.…”

Section: Discussionmentioning

confidence: 91%

PBRM1 loss is associated with increased sensitivity to MCL1 and CDK9 inhibition in clear cell renal cancer

Fultang,

Schwab,

McAneny-Droz

et al. 2024

Front. Oncol.

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MCL1 is a member of the BCL2 family of apoptosis regulators, which play a critical role in promoting cancer survival and drug resistance. We previously described PRT1419, a potent, MCL1 inhibitor with anti-tumor efficacy in various solid and hematologic malignancies. To identify novel biomarkers that predict sensitivity to MCL1 inhibition, we conducted a gene essentiality analysis using gene dependency data generated from CRISPR/Cas9 cell viability screens. We observed that clear cell renal cancer (ccRCC) cell lines with damaging PBRM1 mutations displayed a strong dependency on MCL1. PBRM1 (BAF180), is a chromatin-targeting subunit of mammalian pBAF complexes. PBRM1 is frequently altered in various cancers particularly ccRCC with ~40% of tumors harboring damaging PBRM1 alterations. We observed potent inhibition of tumor growth and induction of apoptosis by PRT1419 in various preclinical models of PBRM1-mutant ccRCC but not PBRM1-WT. Depletion of PBRM1 in PBRM1-WT ccRCC cell lines induced sensitivity to PRT1419. Mechanistically, PBRM1 depletion coincided with increased expression of pro-apoptotic factors, priming cells for caspase-mediated apoptosis following MCL1 inhibition. Increased MCL1 activity has been described as a resistance mechanism to Sunitinib and Everolimus, two approved agents for ccRCC. PRT1419 synergized with both agents to potently inhibit tumor growth in PBRM1-loss ccRCC. PRT2527, a potent CDK9 inhibitor which depletes MCL1, was similarly efficacious in monotherapy and in combination with Sunitinib in PBRM1-loss cells. Taken together, these findings suggest PBRM1 loss is associated with MCL1i sensitivity in ccRCC and provide rationale for the evaluation of PRT1419 and PRT2527 for the treatment for PBRM1-deficient ccRCC.

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“…Further work is needed to determine if BCL-XL is required for RCC metastatic seeding of the CNS and is a brain metastases-specific vulnerability, especially as BCL-XL protein levels did not appear predictive of response to BCL-XL inhibitors in the aforementioned study. 47 STING levels were higher in extracranial metastases relative to brain metastases in all compartments, most prominently in CD45+ leucocytes. The cGAS-STING pathway can inhibit tumor growth by activating interferon signaling and immune surveillance, although it is increasingly recognized as also having protumorigenic and metastasis-promoting functions, depending on the context, such as more advanced stages of disease when cancer cells can become tolerant of chronic inflammatory signaling and even use it to drive metastasis.…”

Section: Open Accessmentioning

confidence: 87%

“…Interestingly, BCL-XL was recently identified as a genetic dependency in kidney cancer cell lines that possessed a mesenchymal gene signature. 47 Pharmacological or genetic inhibition of BCL-XL in dependent cells lines led to antitumor effects, and a ‘BCL-XL dependency’ signature was identified in a substantial proportion (~30%) of RCC patients and was associated with worse clinical outcomes, supporting the further exploration of BCL-XL inhibitors in RCC. Our data suggest that BCL-XL expression may be specifically enriched in RCC brain metastases.…”

Section: Discussion/conclusionmentioning

confidence: 98%

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Immune dysfunction revealed by digital spatial profiling of immuno-oncology markers in progressive stages of renal cell carcinoma and in brain metastases

Schoenfeld

Moutafi

Martínez

et al. 2023

J Immunother Cancer

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BackgroundThe tumor microenvironment (TME) contributes to cancer progression and treatment response to therapy, including in renal cell carcinoma (RCC). Prior profiling studies, including single-cell transcriptomics, often involve limited sample sizes and lack spatial orientation. The TME of RCC brain metastases, a major cause of morbidity, also remains largely uncharacterized.MethodsWe performed digital spatial profiling on the NanoString GeoMx platform using 52 validated immuno-oncology markers on RCC tissue microarrays representing progressive stages of RCC, including brain metastases. We profiled 76 primary tumors, 27 adjacent histologically normal kidney samples, and 86 metastases, including 24 brain metastases.ResultsWe observed lower immune checkpoint (TIM-3 and CTLA-4), cytolytic (GZMA and GZMB), and T cell activation (CD25) protein expression in metastases compared with primary tumors in two separate cohorts. We also identified changes in macrophages in metastases, with brain metastases-susceptible patients showing less M1-like, inflammatory macrophage markers (HLA-DR and CD127) in metastatic samples. A comparison of brain metastases to extracranial metastases revealed higher expression of the anti-apoptotic, BCL-2-family protein BCL-XL and lower expression of the innate immune activator STING in brain metastases. Lower TIM-3 and CD40 in the TME of brain metastases appear to be associated with longer survival, a finding that requires further validation.ConclusionsCompared with primary tumors, RCC metastases, including brain metastases, express lower levels of numerous markers of immune activation and current or investigational therapeutic targets. Our findings may have important implications for designing future biomarker and treatment studies and may aid in development of brain metastases-specific therapies.

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A Mesenchymal Tumor Cell State Confers Increased Dependency on the BCL-XL Antiapoptotic Protein in Kidney Cancer

Cited by 9 publications

References 49 publications

Deep Biological Pathway Informed Pathology-Genomic Multimodal Survival Prediction

Deep Biological Pathway Informed Pathology-Genomic Multimodal Survival Prediction

PBRM1 loss is associated with increased sensitivity to MCL1 and CDK9 inhibition in clear cell renal cancer

Immune dysfunction revealed by digital spatial profiling of immuno-oncology markers in progressive stages of renal cell carcinoma and in brain metastases

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