Altered RNA Splicing by Mutant p53 Activates Oncogenic RAS Signaling in Pancreatic Cancer

Escobar‐Hoyos, Luisa F.; Penson, Alex; Kannan, Ram; Cho, Hanna; Pan, Chun‐Hao; Singh, Rohit; Apken, Lisa H.; Hobbs, G. Aaron; Luo, Renhe; Lecomte, Nicolas; Babu, Sruthi; Pan, Fong Cheng; Alonso-Curbelo, Direna; Morris, John P.; Aşkan, Gökçe; Grbovic-Huezo, Olivera; Ogrodowski, Paul; Bermeo, Jonathan; Saglimbeni, Joseph A.; Cruz, Cristian D.; Ho, Yu-Jui; Lawrence, Scott L.; Melchor, Jerry P.; Goda, Grant A.; Bai, Karen; Pastore, Alessandro; Hogg, Simon J.; Raghavan, Srivatsan; Bailey, Peter J.; Chang, David K.; Biankin, Andrew V.; Shroyer, Kenneth R.; Wolpin, Brian M.; Aguirre, Andrew J.; Ventura, Andrea; Taylor, Barry S.; Der, Channing J.; Domínguez, Daniel; Kümmel, Daniel; Oeckinghaus, Andrea; Lowe, Scott W.; Bradley, Robert K.; Abdel‐Wahab, Omar; Leach, Steven D.

doi:10.1016/j.ccell.2020.05.010

Cited by 114 publications

(113 citation statements)

References 62 publications

(83 reference statements)

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“…These mutations may change the sensitivity to signal transduction pathways inhibitors. There are also interactions between GSK-3, NF-κB, and TP53, which alter the sensitivity to signal transduction inhibitors [44,[56][57][58][59][60][61][62][63]. GSK-3 can affect the activity of NF-κB by phosphorylation of the IKKγ/NEMO substrate [61].…”

Section: Effects Of Wt-gsk-3β and Kd-gsk-3β On Sensitivities Of Mia-pmentioning

confidence: 99%

GSK-3β Can Regulate the Sensitivity of MIA-PaCa-2 Pancreatic and MCF-7 Breast Cancer Cells to Chemotherapeutic Drugs, Targeted Therapeutics and Nutraceuticals

Abrams

Akula

Meher

et al. 2021

Cells

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Glycogen synthase kinase-3 (GSK-3) is a regulator of signaling pathways. KRas is frequently mutated in pancreatic cancers. The growth of certain pancreatic cancers is KRas-dependent and can be suppressed by GSK-3 inhibitors, documenting a link between KRas and GSK-3. To further elucidate the roles of GSK-3β in drug-resistance, we transfected KRas-dependent MIA-PaCa-2 pancreatic cells with wild-type (WT) and kinase-dead (KD) forms of GSK-3β. Transfection of MIA-PaCa-2 cells with WT-GSK-3β increased their resistance to various chemotherapeutic drugs and certain small molecule inhibitors. Transfection of cells with KD-GSK-3β often increased therapeutic sensitivity. An exception was observed with cells transfected with WT-GSK-3β and sensitivity to the BCL2/BCLXL ABT737 inhibitor. WT-GSK-3β reduced glycolytic capacity of the cells but did not affect the basal glycolysis and mitochondrial respiration. KD-GSK-3β decreased both basal glycolysis and glycolytic capacity and reduced mitochondrial respiration in MIA-PaCa-2 cells. As a comparison, the effects of GSK-3 on MCF-7 breast cancer cells, which have mutant PIK3CA, were examined. KD-GSK-3β increased the resistance of MCF-7 cells to chemotherapeutic drugs and certain signal transduction inhibitors. Thus, altering the levels of GSK-3β can have dramatic effects on sensitivity to drugs and signal transduction inhibitors which may be influenced by the background of the tumor.

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Section: Effects Of Wt-gsk-3β and Kd-gsk-3β On Sensitivities Of Mia-pmentioning

confidence: 99%

GSK-3β Can Regulate the Sensitivity of MIA-PaCa-2 Pancreatic and MCF-7 Breast Cancer Cells to Chemotherapeutic Drugs, Targeted Therapeutics and Nutraceuticals

Abrams

Akula

Meher

et al. 2021

Cells

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“…By regulating the alternative splicing of GAPs, mutp53 would contribute to maximal activity of mutant K-Ras, enhancing its oncogenic potential. This model was supported by experiments in PDAC preclinical models [ 105 ].…”

Section: Post-transcriptional Inhibition Of Rasgaps In Cancermentioning

confidence: 79%

“…Finally, a recent study uncovered a mechanism by which the splicing of GAPs can be reprogrammed to foster Ras activation in pancreatic ductal adenocarcinoma (PDAC) [ 105 ]. Specifically, expression of oncogenic p53 mutant proteins (mutp53) promotes the inclusion of cytosine-rich exons within the mRNA of multiple GAPs, resulting in defective Ras inhibition.…”

Section: Post-transcriptional Inhibition Of Rasgaps In Cancermentioning

confidence: 99%

Cutting the Brakes on Ras—Cytoplasmic GAPs as Targets of Inactivation in Cancer

Bellazzo

Collavin

2020

Cancers

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The Ras pathway is frequently deregulated in cancer, actively contributing to tumor development and progression. Oncogenic activation of the Ras pathway is commonly due to point mutation of one of the three Ras genes, which occurs in almost one third of human cancers. In the absence of Ras mutation, the pathway is frequently activated by alternative means, including the loss of function of Ras inhibitors. Among Ras inhibitors, the GTPase-Activating Proteins (RasGAPs) are major players, given their ability to modulate multiple cancer-related pathways. In fact, most RasGAPs also have a multi-domain structure that allows them to act as scaffold or adaptor proteins, affecting additional oncogenic cascades. In cancer cells, various mechanisms can cause the loss of function of Ras inhibitors; here, we review the available evidence of RasGAP inactivation in cancer, with a specific focus on the mechanisms. We also consider extracellular inputs that can affect RasGAP levels and functions, implicating that specific conditions in the tumor microenvironment can foster or counteract Ras signaling through negative or positive modulation of RasGAPs. A better understanding of these conditions might have relevant clinical repercussions, since treatments to restore or enhance the function of RasGAPs in cancer would help circumvent the intrinsic difficulty of directly targeting the Ras protein.

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“…PDA cells harboring TP53 missense mutations exhibited aberrant use of exons compared with wild-type or harboring truncating mutations. In particular, the TP53 R175H mutant regulates the expression of specific GTPase-activating protein isoforms (GAPs) in pancreatic cancer as a consequence of altered alternative splicing [29]. Other hotspot mutants, such as TP53 R273H , which inhibits the expression of KLF6, promote migration and metastasis [30].…”

Section: Tp53mentioning

confidence: 99%

Molecular Alterations in Pancreatic Cancer: Transfer to the Clinic

Gil

Sánchez

Velasco

et al. 2021

IJMS

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Pancreatic ductal adenocarcinoma (PDA) is the most common cancer of the exocrine pancreas and probably the tumor that has benefited the least from clinical progress in the last three decades. A consensus has been reached regarding the histologic classification of the ductal preneoplastic lesions (pancreatic intra-epithelial neoplasia—PanIN) and the molecular alterations associated with them. Mutations in KRAS and inactivation of CDKN2A, SMAD4 and TP53 are among the most prevalent alterations. Next generation sequencing studies are providing a broad picture of the enormous heterogeneity in this tumor type, describing new mutations less prevalent. These studies have also allowed the characterization of different subtypes with prognostic value. However, all this knowledge has not been translated into a clinical progress. Effective preventive and early diagnostic strategies are essential to improve the survival rates. The main challenge is, indeed, to identify new effective drugs. Despite many years of research and its limited success, gemcitabine is still the first line treatment of PDA. New drug combinations and new concepts to improve drug delivery into the tumor, as well as the development of preclinical predictive assays, are being explored and provide optimism and prospects for better therapies.

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Altered RNA Splicing by Mutant p53 Activates Oncogenic RAS Signaling in Pancreatic Cancer

Cited by 114 publications

References 62 publications

GSK-3β Can Regulate the Sensitivity of MIA-PaCa-2 Pancreatic and MCF-7 Breast Cancer Cells to Chemotherapeutic Drugs, Targeted Therapeutics and Nutraceuticals

GSK-3β Can Regulate the Sensitivity of MIA-PaCa-2 Pancreatic and MCF-7 Breast Cancer Cells to Chemotherapeutic Drugs, Targeted Therapeutics and Nutraceuticals

Cutting the Brakes on Ras—Cytoplasmic GAPs as Targets of Inactivation in Cancer

Molecular Alterations in Pancreatic Cancer: Transfer to the Clinic

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