rapalogs can promote cancer cell stemness in vitro in a Galectin-1 and H-ras-dependent manner

Currently several combination treatments of mTor- and Ras-pathway inhibitors
are being tested in cancer therapy. While multiple feedback loops render these central
signaling pathways robust, they complicate drug targeting.
Here, we describe a novel H-ras specific feedback, which leads to an inadvertent
rapalog induced activation of tumorigenicity in Ras transformed cells. We find that
rapalogs specifically increase nanoscale clustering (nanoclustering) of oncogenic
H-ras but not K-ras on the plasma membrane. This increases H-ras signaling output,
promotes mammosphere numbers in a H-ras-dependent manner and tumor growth
in ovo. Surprisingly, also other FKBP12 binders, but not mTor-inhibitors, robustly
decrease FKBP12 levels after prolonged (>2 days) exposure. This leads to an
upregulation of the nanocluster scaffold galectin-1 (Gal-1), which is responsible
for the rapamycin-induced increase in H-ras nanoclustering and signaling output.
We provide evidence that Gal-1 promotes stemness features in tumorigenic cells.
Therefore, it may be necessary to block inadvertent induction of stemness traits in
H-ras transformed cells by specific Gal-1 inhibitors that abrogate its effect on H-ras
nanocluster. On a more general level, our findings may add an important mechanistic
explanation to the pleiotropic physiological effects that are observed with rapalogs.