The p38 MAPK Signaling Activation in Colorectal Cancer upon Therapeutic Treatments

Pranteda, Angelina; Piastra, Valentina; Stramucci, Lorenzo; Fratantonio, Deborah; Bossi, Gianluca

doi:10.3390/ijms21082773

Cited by 42 publications

(34 citation statements)

References 67 publications

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“…High levels of p38 correlate with poor survival in lung adenocarcinoma patients [150]. Of note, studies combining p38 inhibition in conjunction with chemotherapeutic agents such as cisplatin, irinotecan or arsenic trioxide showed opposing results and led to the acceleration of tumor growth upon p38 inhibition [53][54][55]57,[151][152][153]. No p38 inhibitor has been approved for clinical use but clinical trials are ongoing in advanced cancer patients with the p38 inhibitor ralimetinib (Table 3).…”

Section: Mapk As Target In Cancer Therapymentioning

confidence: 99%

CDK4/6 and MAPK—Crosstalk as Opportunity for Cancer Treatment

2020

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Despite the development of targeted therapies and novel inhibitors, cancer remains an undefeated disease. Resistance mechanisms arise quickly and alternative treatment options are urgently required, which may be partially met by drug combinations. Protein kinases as signaling switchboards are frequently deregulated in cancer and signify vulnerable nodes and potential therapeutic targets. We here focus on the cell cycle kinase CDK6 and on the MAPK pathway and on their interplay. We also provide an overview on clinical studies examining the effects of combinational treatments currently explored for several cancer types.

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Section: Mapk As Target In Cancer Therapymentioning

confidence: 99%

CDK4/6 and MAPK—Crosstalk as Opportunity for Cancer Treatment

2020

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“…This increase in stromal cells could be a culprit in treatment resistance, with the proportion of cancer cells to CAFs reaching a state where the secreted EGF levels are sufficient to sustain MAPK signaling in the presence of cetuximab. Combination treatment with MAPK inhibitors may be an attractive target to mitigate CAF-induced cetuximab resistance [22,23]. In recent years, there has also been a push to develop therapeutics that target CAFs [24].…”

Section: Discussionmentioning

confidence: 99%

Anti-EGFR Therapy Induces EGF Secretion by Cancer-Associated Fibroblasts to Confer Colorectal Cancer Chemoresistance

Garvey

Lau

Sanchez

et al. 2020

Cancers

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Targeted agents have improved the efficacy of chemotherapy for cancer patients, however, there remains a lack of understanding of how these therapies affect the unsuspecting bystanders of the stromal microenvironment. Cetuximab, a monoclonal antibody therapy targeting the epidermal growth factor receptor (EGFR), is given in combination with chemotherapy as the standard of care for a subset of metastatic colorectal cancer patients. The overall response to this treatment is underwhelming and, while genetic mutations that confer resistance have been identified, it is still not known why this drug is ineffective for some patients. We discovered that cancer-associated fibroblasts (CAFs), a major cellular subset of the tumor stroma, can provide a source of cancer cell resistance. Specifically, we observed that upon treatment with cetuximab, CAFs increased their secretion of EGF, which was sufficient to render neighboring cancer cells resistant to cetuximab treatment through sustained mitogen-activated protein kinases (MAPK) signaling. Furthermore, we show the cetuximab-induced EGF secretion to be specific to CAFs and not to cancer cells or normal fibroblasts. Altogether, this work emphasizes the importance of the tumor microenvironment and considering the potential unintended consequences of therapeutically targeting cancer-driving proteins on non-tumorigenic cell types.

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“…In agreement with this, increased activity of mTORC1 by PI3K or p38 MAPK kinases has been associated to SGs formation in breast cancer cells[ 16 ]. These pathways are commonly overactive in CRC[ 124 , 125 ], and the downstream activation of mTORC1 may represent an important event triggering SGs assembly in colon cancer cells. The complexity mTORC1 signaling is further enhanced by AMPKα, which is an negative upstream regulator of mTORC1 signaling, in promoting SGs assembly[ 17 ] and is frequently upregulated in CRC[ 126 , 127 ].…”

Section: Role Of Stress Granules In Colorectal Cancermentioning

confidence: 99%

Stress granules in colorectal cancer: Current knowledge and potential therapeutic applications

Legrand¹,

Dixon²,

Sobolewski³

2020

WJG

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Stress granules (SGs) represent important non-membrane cytoplasmic compartments, involved in cellular adaptation to various stressful conditions ( e.g ., hypoxia, nutrient deprivation, oxidative stress). These granules contain several scaffold proteins and RNA-binding proteins, which bind to mRNAs and keep them translationally silent while protecting them from harmful conditions. Although the role of SGs in cancer development is still poorly known and vary between cancer types, increasing evidence indicate that the expression and/or the activity of several key SGs components are deregulated in colorectal tumors but also in pre-neoplastic conditions ( e.g ., inflammatory bowel disease), thus suggesting a potential role in the onset of colorectal cancer (CRC). It is therefore believed that SGs formation importantly contributes to various steps of colorectal tumorigenesis but also in chemoresistance. As CRC is the third most frequent cancer and one of the leading causes of cancer mortality worldwide, development of new therapeutic targets is needed to offset the development of chemoresistance and formation of metastasis. Abolishing SGs assembly may therefore represent an appealing therapeutic strategy to re-sensitize colon cancer cells to anti-cancer chemotherapies. In this review, we summarize the current knowledge on SGs in colorectal cancer and the potential therapeutic strategies that could be employed to target them.

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The p38 MAPK Signaling Activation in Colorectal Cancer upon Therapeutic Treatments

Cited by 42 publications

References 67 publications

CDK4/6 and MAPK—Crosstalk as Opportunity for Cancer Treatment

CDK4/6 and MAPK—Crosstalk as Opportunity for Cancer Treatment

Anti-EGFR Therapy Induces EGF Secretion by Cancer-Associated Fibroblasts to Confer Colorectal Cancer Chemoresistance

Stress granules in colorectal cancer: Current knowledge and potential therapeutic applications

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