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Mitogen-Activated Protein Kinase and Nuclear Hormone Receptor Crosstalk in Cancer Immunotherapy.

ABSTRACT: The three major MAP-kinase (MAPK) pathways, ERK1/2, p38 and JNK/SAPK, are upstream regulators of the nuclear "hormone" receptor superfamily (NHRSF), with a prime example given by the estrogen receptor in breast cancer. These ligand-activated transcription factors exert non-genomic and genomic functions, where they are either post-translationally modified by phosphorylation or directly interact with components of the MAPK pathways, events that govern their transcriptional activity towards target genes involved in cell differentiation, proliferation, metabolism and host immunity. This molecular crosstalk takes place not only in normal epithelial or tumor cells, but also in a plethora of immune cells from the adaptive and innate immune system in the tumor-stroma tissue microenvironment. Thus, the drugability of both the MAPK and the NHRSF pathways suggests potential for intervention therapies, especially for cancer immunotherapy. This review summarizes the existing literature covering the expression and function of NHRSF subclasses in human tumors, both solid and leukemias, and their effects in combination with current clinically approved therapeutics against immune checkpoint molecules (e.g., PD1).

SUBMITTER: Burgermeister E

PROVIDER: S-EPMC10488039 | biostudies-literature | 2023 Sep

REPOSITORIES: biostudies-literature

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Mitogen-Activated Protein Kinase and Nuclear Hormone Receptor Crosstalk in Cancer Immunotherapy.

Burgermeister Elke E

International journal of molecular sciences 20230904 17

The three major MAP-kinase (MAPK) pathways, ERK1/2, p38 and JNK/SAPK, are upstream regulators of the nuclear "hormone" receptor superfamily (NHRSF), with a prime example given by the estrogen receptor in breast cancer. These ligand-activated transcription factors exert non-genomic and genomic functions, where they are either post-translationally modified by phosphorylation or directly interact with components of the MAPK pathways, events that govern their transcriptional activity towards target ...[more]

PMID: 37686465

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Project description:BackgroundThe mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) pathway plays an important role in papillary and anaplastic thyroid cancer (PTC and ATC) due to activating mutations in BRAF, RAS, or rearrangements in RET/PTC1. The objective of this study was to thoroughly test whether the BRAF V600E mutation predicts response to mitogen-activated protein kinase kinase 1/2 (MKK1/2) inhibition, as shown in other tumor types, using an authenticated panel of thyroid cancer cell lines.MethodsPTC and ATC cells harboring distinct mutations in the MAPK pathway were treated with two different inhibitors selective for MKK1/2 (CI-1040 or U0126). The consequences of MKK1/2 inhibition on cell growth, survival, invasion, and MAPK signaling was determined.ResultsInhibition of MKK1/2 using CI-1040 or U0126 differentially inhibits the growth of a panel of PTC and ATC cell lines in two-dimensional culture, with those harboring the BRAF V600E mutation (SW1736) or BRAF-V600E/PI3K-E542K mutations (K1) being the most sensitive, the RET/PTC1 rearrangement (TPC1) and BRAF V600E mutant (BCPAP), intermediate, and the HRAS-G13R mutant (C643), the least sensitive. Growth of these cells is more sensitive to MKK1/2 inhibition when grown in 2% versus 10% serum. Baseline levels of phospho-ERK1/2 were similar in all of the cell lines, and inhibition phospho-ERK1/2 did not predict sensitivity to MKK1/2 inhibition. When cells are grown in three-dimensional culture, MKK1/2 inhibition of growth correlates with mutational status (BRAF > RET/PTC1 > RAS). Finally, PTC and ATC invasiveness is differentially inhibited by CI-1040, which is independent of tumor type or mutation present.ConclusionsDifferent mutations in the MAPK pathway play distinct roles in the growth and invasion of thyroid cancer cells. These results indicate that MKK1/2 inhibitors have the potential to inhibit thyroid cancer growth and invasion, but that responses differ based on mutation status and growth conditions.

Dataset Information

Mitogen-Activated Protein Kinase and Nuclear Hormone Receptor Crosstalk in Cancer Immunotherapy.

Publications

Mitogen-Activated Protein Kinase and Nuclear Hormone Receptor Crosstalk in Cancer Immunotherapy.

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