CD44/HA signaling mediates acquired resistance to a PI3Kα inhibitor

Most luminal breast carcinomas (BrCas) bearing PIK3CA mutations initially respond to phosphoinositide-3-kinase (PI3K)-α inhibitors, but many eventually become resistant. The underlying mechanisms of this resistance remain obscure. In this work, we showed that a CD44(high) state due to aberrant isoform splicing was acquired from adaptive resistance to a PI3Kα inhibitor (BLY719) in luminal BrCas. Notably, the expression of CD44 was positively correlated with estrogen receptor (ER) activity in PIK3CA-mutant breast cancers, and ER-dependent transcription upon PI3Kα pathway inhibition was in turn mediated by CD44. Furthermore, the interaction of CD44 with the ligand hyaluronan (HA) initiated the Src-ERK signaling cascade, which subsequently maintained AKT and mTOR activity in the presence of a PI3Kα inhibitor. Activation of this pathway was prevented by disruption of the CD44/HA interaction, which in turn restored sensitivity to BLY719. Our results revealed that an ER-CD44-HA signaling circuit that mediates robust compensatory activation of the Src-ERK signaling cascade may contribute to the development of acquired resistance to PI3Kα inhibitors. This study provides new insight into the mechanism of adaptive resistance to PI3Kα inhibition therapy.