CD44/HA signaling mediates acquired resistance to a PI3Kα inhibitor

Abstract

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 CD44high 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.

Loss of HAS2 Confers Acquired Antiestrogen Resistance by Upregulating Ezrin Expression in ER-Positive Breast Cancer

“…It is also well documented that Has2 might be a potential therapeutic target via Has2 inhibitor [31]. Moreover, from our recent study, luminallike breast cancer cells preferentially express Has2 or ER with a positive association under pressure of PI3Kα-inhibitory chemotherapy [32]. Taken together, we hypothesize that there might be a potentially novel relationship of ER and Has2 during the development of endocrine therapy resistance.…”

“…Previous studies have indicated that the expression of Has2 was easily in uenced by hormones, including estrogen, and contributed to changes of cell state [25,40]. Moreover, our recent reports identi ed Has2 as a rapid responsive gene upon drug therapy in breast cancer [32]. For the rst time, we demonstrated that Has2 loss was a rapid response to endocrine therapy and played an important role in the acquisition of endocrine resistance.…”

“…First, we sought to determine if there was evidence for Ezrin upregulation in ER-positive tumors from patients. Our previous report has revealed that Ezrin is overexpressed in primary invasive BrCas compared with normal mammary tissues from TCGA data [32]. Here, a higher level of Ezrin was observed in luminal-like BrCa compared to Her2-positive and triple-negative BrCa tissues (Fig.…”

“…Based on previous observations related to Has2 gene where it is readily to be regulated by hormone-type effectors [18][19][20], and related to cell plasticity [30,32], its role in development of endocrine resistance is likely to be emerging. The speci c association between Has2 and ER were in our cohort is consistent with the analysis of TCGA data broadly.…”

The plasticity of pancreatic cancer stem cells: implications in therapeutic resistance

“…This ubiquitous transmembrane molecule is preferentially upregulated in a range of tumors, particularly, in TICs and drug-resistant tumor lesions [ 76 ]. During tumorigenesis, CD44 undergoes extensive alternative splicing generating two isoforms with overlapping and distinct cellular functions: the CD44 variant (CD44v) and CD44 standard (CD44s) isoform [ 77 ]. Although the functional significance of distinct CD44 isoforms in the pathogenesis of cancer is under investigation, the dysregulation of isoform switching has been determined [ 77 ] and implicated in regulating EMT and the adaptive plasticity of cancer cells [ 75 ], potentially generating adaptive therapeutic resistance and tumor recurrence [ 78 ].…”