Targeting CXCR4–CXCL12–CXCR7 axis combats mTOR inhibitor resistance in renal cancer

By Afsaneh Gray, medwireNews Reporter

There is considerable crosstalk between the CXCR4–CXCL12–CXCR7 axis and the mammalian target of rapamycin (mTOR) pathway in human renal cell carcinoma (RCC), and targeting the axis may overcome drug resistance to mTOR inhibitors, researchers suggest.

“Although mTOR inhibitors prolong progression-free survival in patients with advanced RCC, most patients develop resistance to mTOR-inhibiting agents, limiting their efficacy,” say Stefania Scala (Istituto Nazionale per lo Studio e la Cura dei Tumori, Naples, Italy) and colleagues. “[T]he new frontier of inhibiting the mTOR pathway is to identify agents targeting the feedback loops and crosstalks with other pathways involved in the acquired resistance to mTOR inhibitors”, they add.

Chemokines and their receptors have previously been implicated in regulating RCC growth, angiogenesis and metastasis, they point out, making the CXCL12–CXCR4–CXCR7 chemokine receptor axis an attractive target for research.

To evaluate the role of CXCR4 in mTOR signaling, the team used two human RCC cell lines: A498, which expresses high levels of CXCR4; and SN12C, with low CXCR4 expression. They found that treatment with CXCL12 induced expression of two mTOR target proteins in both cell lines, and that a CXCR4 antagonist inhibited this induction, suggesting that CXCL12 signals to mTOR.

Scala and co-workers next looked at the role of CXCR7 on the mTOR pathway by stimulating SN12C and A498 cells with CXCL12, or with the exclusive CXCR7 ligand CXCL11, in the presence of a CXCR7 inhibitor. CXCL11-mediated induction of two downstream proteins was inhibited only by the CXCR7 inhibitor, suggesting that mTOR inhibition is also downstream of CXCR7.

The researchers also investigated the role of CXCR4, CXCR7 and mTOR in cell migration and wound healing. They found that SN12C and A498 cells migrated towards CXCL12 and CXCL11, with CXCR4 and CXCR7 inhibitors impairing this process. Treatment with the mTOR inhibitor RAD001 further disrupted migration. CXCL12 and CXCL11 also induced wound healing, which was impaired by a CXCR7 antagonist and RAD001.

Similarly, when cell growth was evaluated in the presence of CXCL12, CXCL11 and mTOR inhibitors, the effect of the inhibitors was found to be additive. Finally, the researchers note that SN12C and A498 cells that were resistant to the mTOR inhibitor RAD001 recovered their drug sensitivity in the presence of CXCR4 and CXCR7 antagonists.

Writing in Cell Death and Disease, they conclude: “The entire […] CXCR4–CXCL12–CXCR7 [axis] regulates mTOR signaling in renal cancer cells, offering new therapeutic opportunities and targets to overcome resistance to mTOR inhibitors.”

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