Macrophages confer resistance to PI3K inhibitor GDC-0941 in breast cancer through the activation of NF-κB signaling

Abstract

The PI3K pathway is one of the most dysregulated signaling pathways in epithelial cancers and has become an attractive therapeutic target under active preclinical and clinical development. However, recent clinical trial studies revealed that blockade of PI3K activity in advanced cancer often leads to the development of resistance and relapse of the diseases. Intense efforts have been made to elucidate resistance mechanisms and identify rational drug combinations with PI3K inhibitors in solid tumors. In the current study, we found that PI3K inhibition by GDC-0941 increased macrophage infiltration and induced the expression of macrophage-associated cytokines and chemokines in the mouse 4T1 breast tumor model. Using the in vitro co-culture system, we showed that the presence of macrophages led to the activation of NF-κB signaling in 4T1 tumor cells, rendering tumor cells resistant to PI3K inhibition by GDC-0941. Furthermore, we found that Aspirin could block the activation of NF-κB signaling induced by PI3K inhibition, and combined use of GDC-0941 and Aspirin resulted in attenuated cell growth and enhanced apoptosis of 4T1 cells in the in vitro co-culture system with the presence of macrophages. Consistently, the combination treatment also effectively reduced tumor burden, macrophage infiltration and pulmonary metastasis in in vivo 4T1 breast tumor model. Together, our results suggested macrophages in microenvironment may contribute to the resistance of breast cancer cells to PI3K inhibition and reveal a new combination paradigm to improve the efficacy of PI3K-targeted therapy.

The active fraction of Garcinia yunnanensis suppresses the progression of colorectal carcinoma by interfering with tumorassociated macrophage‐associated M2 macrophage polarization in vivo and in vitro

“…Similar to Flow cytometric analysis, YTE‐17 significantly restrained M2 marker (Arg‐1) and enhanced M1 marker (iNOS) expression, respectively (Figure 3B up). Extensive evidence suggests that the phosphorylation of some known signaling pathways, including ERK, JNK, and STAT3, is markedly enhanced by tumor supernatant stimulation in RAW264.7 cells 34-36 . To further explore the potential mechanism of YTE‐17, we used in vitro models to identify the pathway that could be regulated as YTE‐17 inhibits M2 macrophage polarization.…”

Repression of AXL expression by AP-1/JNK blockage overcomes resistance to PI3Ka therapy

“…A number of studies have shown that overexpression of AXL in response to therapeutic stress can evolve through a variety of mechanisms, including transcriptional regulation (15,23,24,(49)(50)(51), posttranslational regulation (52,53), and expression of miRNA (54) cytokines, such as TNF-α following anti-PI3K treatment (57), it is tempting to suggest that BYL719 treatment induces the secretion of proinflammatory cytokines, which may downregulate MITF expression and, hence, enhance c-JUN expression.…”

Tumor Necrosis Factor α Blockade: An Opportunity to Tackle Breast Cancer

“…Experiments performed in vivo proved that pictisilib administration induced the expression of macrophage-associated cytokines and chemokines, macrophage recruitment to the tumor bed, and poor antitumor effect. However, treatment with aspirin and pictisilib decreased macrophage infiltration, tumor growth and pulmonary metastasis (214), highlighting the importance of macrophage-induced NF-κB activation in tumor cells resistant to pictisilib. In line with these findings, TNFα derived from macrophages, turned melanoma cells resistant to MEK inhibition through activation of NF-κB (215).…”