SWATH-MS proteomics of PANC-1 and MIA PaCa-2 pancreatic cancer cells allows identification of drug targets alternative to MEK and PI3K inhibition

Aguilar‐Valdés, Alain; Noriega, Lilia G.; Tovar, Armando R.; Ibarra-Sánchez, Marı́a de Jesús; Sosa-Hernández, Víctor Andrés; Maravillas-Montero, José Luis; Martínez‐Aguilar, Juan

doi:10.1016/j.bbrc.2021.03.018

Cited by 4 publications

(5 citation statements)

References 27 publications

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“…Remarkably, several DEPs found in this work associated with adaptive resistance to MEK and PI3K inhibition, namely cav‐1, cavin‐3, IGF2R, serpin B9, fln‐a, rabaptin‐5 and podocalyxin, have previously been found in our work on pancreatic cancer cells with intrinsic resistance to the same combination therapy [56], which suggests a proteomic signature of MEKi + PI3Ki resistance in PDAC cells. Some of their main known roles in cancer are discussed below.…”

Section: Discussionsupporting

confidence: 67%

“…More timecontrolled experiments are needed to decipher the regulation of cav-1 by statins in the resistant cells.Remarkably, several DEPs found in this work associated with adaptive resistance to MEK and PI3K inhibition, namely cav-1, cavin-3, IGF2R, serpin B9, fln-a, rabaptin-5 and podocalyxin, have previously been found in our work on pancreatic cancer cells with intrinsic resistance to the same combination therapy[56], which suggests a proteomic signature of MEKi + PI3Ki resistance in PDAC cells. Some of their main known roles in cancer are discussed below.Cav-1 is an essential component of caveolae involved in endocytosis, lipid homeostasis and signal transduction.…”

supporting

confidence: 72%

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A proteomic signature and potential pharmacological opportunities in the adaptive resistance to MEK and PI3K kinase inhibition in pancreatic cancer cells

et al. 2023

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Pancreatic cancer is one of the most lethal cancer types and is becoming a leading cause of cancer‐related deaths. The limited benefit offered by chemotherapy agents has propelled the search for alternative approaches that target specific molecular drivers of cancer growth and progression. Mutant KRas and effector pathways Raf/MEK/ERK and PI3K/Akt are key players in pancreatic cancer; however, preclinical studies have shown adaptive tumour response to combined MEK and PI3K kinase inhibition leading to treatment resistance. There is a critical unmet need to decipher the molecular basis underlying adaptation to this targeted approach. Here, we aimed to identify common protein expression alterations associated with adaptive resistance in KRas‐mutant pancreatic cancer cells, and test if it can be overcome by selected already available small molecule drugs. We found a group of 14 proteins with common expression change in resistant cells, including KRas, caveolin‐1, filamin‐a, eplin, IGF2R and cytokeratins CK‐8, ‐18 and ‐19. Notably, several proteins have previously been observed in pancreatic cancer cells with intrinsic resistance to the combined kinase inhibition treatment, suggesting a proteomic signature. We also found that resistant cells are sensitive to small molecule drugs ERK inhibitor GDC‐0994, S6K1 inhibitor DG2 and statins.

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Section: Discussionsupporting

confidence: 67%

supporting

confidence: 72%

A proteomic signature and potential pharmacological opportunities in the adaptive resistance to MEK and PI3K kinase inhibition in pancreatic cancer cells

et al. 2023

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“…On the other hand, IACS-010759 has shown significant cell viability reduction in PCA cell lines[ 279 ], leading to the initiation of a Phase I clinical trial (NCT03291938) to evaluate clinical efficacy and safety in patients with solid tumors due to CCA, PAC, and CRC. However, a recent publication reported that although IACS-010759 was tolerable and safe, it increased blood lactate levels and neurotoxicity while offering only limited anti-cancer efficacy.…”

Section: Targeting Oxphos As a Potential Therapeutic Strategy For Gi ...mentioning

confidence: 99%

Bioenergetic alteration in gastrointestinal cancers: The good, the bad and the ugly

Chu¹,

Chen²,

Lai³

et al. 2023

World J Gastroenterol

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Tumor necrosis factor-α (TNF-α) antagonists, the first biologics approved for treating patients with inflammatory bowel disease (IBD), are effective for the induction and maintenance of remission and significantly improving prognosis. However, up to one-third of treated patients show primary nonresponse (PNR) to anti-TNF-α therapies, and 23%-50% of IBD patients experience loss of response (LOR) to these biologics during subsequent treatment. There is still no recognized predictor for evaluating the efficacy of anti-TNF drugs. This review summarizes the existing predictors of PNR and LOR to anti-TNF in IBD patients. Most predictors remain controversial, and only previous surgical history, disease manifestations, drug concentrations, antidrug antibodies, serum albumin, some biologic markers, and some genetic markers may be potentially predictive. In addition, we also discuss the next steps of treatment for patients with PNR or LOR to TNF antagonists. Therapeutic drug monitoring plays an important role in treatment selection. Dose escalation, combination therapy, switching to a different anti-TNF drug, or switching to a biologic with a different mechanism of action can be selected based on the concentration of the drug and/or antidrug antibodies.

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“…In addition, one study identified PP2A as an alternative drug target for cells that have shown resistance to the inhibition of other components of the MAPK pathway in PANC-1 pancreatic cancer cells. A PP2A activator, DT-061, was able to decrease the viability of these cells, along with reducing c-Myc expression [ 37 ].…”

Section: The P38 Mapk Pathwaymentioning

confidence: 99%

The p38 MAPK Components and Modulators as Biomarkers and Molecular Targets in Cancer

García-Hernández

García-Ortega

Ruiz-Alcalá

et al. 2021

IJMS

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The mitogen-activated protein kinase (MAPK) family is an important bridge in the transduction of extracellular and intracellular signals in different responses at the cellular level. Within this MAPK family, the p38 kinases can be found altered in various diseases, including cancer, where these kinases play a fundamental role, sometimes with antagonistic mechanisms of action, depending on several factors. In fact, this family has an immense number of functionalities, many of them yet to be discovered in terms of regulation and action in different types of cancer, being directly involved in the response to cancer therapies. To date, three main groups of MAPKs have been identified in mammals: the extracellular signal-regulated kinases (ERK), Jun N-terminal kinase (JNK), and the different isoforms of p38 (α, β, γ, δ). In this review, we highlight the mechanism of action of these kinases, taking into account their extensive regulation at the cellular level through various modifications and modulations, including a wide variety of microRNAs. We also analyze the importance of the different isoforms expressed in the different tissues and their possible role as biomarkers and molecular targets. In addition, we include the latest preclinical and clinical trials with different p38-related drugs that are ongoing with hopeful expectations in the present/future of developing precision medicine in cancer.

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SWATH-MS proteomics of PANC-1 and MIA PaCa-2 pancreatic cancer cells allows identification of drug targets alternative to MEK and PI3K inhibition

Cited by 4 publications

References 27 publications

A proteomic signature and potential pharmacological opportunities in the adaptive resistance to MEK and PI3K kinase inhibition in pancreatic cancer cells

A proteomic signature and potential pharmacological opportunities in the adaptive resistance to MEK and PI3K kinase inhibition in pancreatic cancer cells

Bioenergetic alteration in gastrointestinal cancers: The good, the bad and the ugly

The p38 MAPK Components and Modulators as Biomarkers and Molecular Targets in Cancer

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