Lehrstuhl für Physiologische Chemie

    Targeted therapy: Pathway inhibition and crosstalk

    Activation of the MAPK pathway is commonly observed in human melanomas. Our data show that this pathway is of high importance for stimulating tumor cells in an autocrine manner – either by induction of the matrix metalloprotease MMP13, or by enhancing transcription of EGFR ligands which both leads to autocrine signaling loops (Meierjohann et al., Mol Cancer, 2010; Laisney et al., Oncogene, 2012).

    In BRAFV600E-positive melanoma patients, treatment with BRAF- or MEK inhibitors have led to significant improvement of overall survival and thus constitutes one of the most successful treatment strategies since decades. However, tumor resistance against inhibitors occurs in most cases. We have found that the BRAF inhibitor vemurafenib not only induces apoptosis, but also leads to the development of long-lived senescent cells (Figure 1) (Haferkamp et al., J Invest Dermatol, 2013).

    Although they are growth-arrested, senescent cells are metabolically active and secrete several pro-tumorigenic factors, which can stimulate adjacent non-senescent cells such as fibroblasts (unpublished data). Therefore, they pose a risk factor for the development of inhibitor resistance. Inhibition of specific receptor tyrosine kinases, which are located downstream of the factors secreted after BRAF inhibition, can prevent this effect and enhance the sensitivity towards BRAF inhibitor.

    Figure 1: Schematic representation of the events following BRAF inhibition in melanoma cells

    These results stress the importance of combination strategies for melanoma therapy. Next to combining two targeted inhibitors, the combination of a targeted inhibitor with chemotherapy is discussed as anti-tumor strategy. We have tested the combination of MEK inhibitors with an inducer of genotoxic stress in a large panel of melanoma cell lines. In three thirds of the cell lines, MEK inhibitor sensitized the cell lines towards cisplatin. However, one quarter of cell lines showed the opposite effect. This is caused by crosstalk activation of the EGFR/RAS/PI3K pathway and ultimately leads to a reduction of pro-apoptotic mediators such as PUMA (Figure 2) (Haydn et al., Oncotarget, 2014). Thus, MEK inhibitors can paradoxically protect melanoma cells from the pro-apoptotic effects of genotoxic stress, if they act in the context of specific receptors such as the EGFR. This implies a careful choice of pathway inhibitors in combination therapies.

    Figure 2: Scheme of the crosstalk mechanism. Left: Under normal conditions, activation of BRAFV600E results in ERK1/2-dependent induction of the negative feedback components SPRED1 and -2, which inhibit RAS signaling downstream of RTKs such as the EGFR. As a consequence, the PI3K pathway is suppressed. In presence of genotoxic stress such as cisplatin, pro-apoptotic PUMA is induced, driving the cells into apoptosis. Right: Under conditions of MEK inhibition, SPRED1 and SPRED2 expression is relieved, and the negative feedback on RTK signaling is abolished. This results in activation of the PI3K pathway, which suppresses pro-apoptotic PUMA in presence of genotoxic stress. Paraxodically, the combined MEK inhibitor and cisplatin treatment. Derived in modified form from: Haydn et al., Oncotarget, 2014.

    The aim of our current research is to interfere with the protective events elicited by inhibitors of the RAF/MEK/MAPK pathway and thereby drive the cells efficiently into apoptosis. When translated into the clinic, this could lead to long-lasting tumor control.


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