Phosphoinositide Conversion Inactivates R‐RAS and Drives Metastases in Breast Cancer

Abstract

Breast cancer is the most prevalent cancer and a major cause of death in women worldwide. Although early diagnosis and therapeutic intervention significantly improve patient survival rate, metastasis still accounts for most deaths. Here it is reported that, in a cohort of more than 2000 patients with breast cancer, overexpression of PI3KC2α occurs in 52% of cases and correlates with high tumor grade as well as increased probability of distant metastatic events, irrespective of the subtype. Mechanistically, it is demonstrated that PI3KC2α synthetizes a pool of PI(3,4)P2 at focal adhesions that lowers their stability and directs breast cancer cell migration, invasion, and metastasis. PI(3,4)P2 locally produced by PI3KC2α at focal adhesions recruits the Ras GTPase activating protein 3 (RASA3), which inactivates R‐RAS, leading to increased focal adhesion turnover, migration, and invasion both in vitro and in vivo. Proof‐of‐concept is eventually provided that inhibiting PI3KC2α or lowering RASA3 activity at focal adhesions significantly reduces the metastatic burden in PI3KC2α‐overexpressing breast cancer, thereby suggesting a novel strategy for anti‐breast cancer therapy.

METTL3/YTHDF2 m6A axis promotes the malignant progression of bladder cancer by epigenetically suppressing RRAS

“…The bioinformatics analysis suggested RRAS as a potential downstream target of METTL3. RRAS has important biological roles in breast cancer ( 44 ), gastric cancer ( 45 ), colorectal cancer ( 46 ) and melanoma ( 47 ). However, its role in BCa remains unclear.…”

Beyond PI3Ks: targeting phosphoinositide kinases in disease

“…However, it should be noted that the scaffold function of PI3KC2α in the clathrin-TACC3 complex has not been observed in other cell types 215 . A catalytic function of PI3KC2α has also been reported, wherein the helical bundle domain targets the kinase to focal adhesions in breast cancer cells, where the resulting PI(3,4)P 2 stimulates turnover, promoting metastasis 210 . Promisingly, this enhanced metastatic potential can be blocked with a PI3KC2α inhibitor (PITCOIN1).…”

“…Initial inhibitors for PI3KC2s were developed from derivatives of the class I PI3K inhibitor PIK-90, leading to the 4-aminonicotinamide derivative MIPS-19416, which display potency against PI3KC2α and PI3KC2β, but with only modest selectivity over class I enzymes 209 (Table 3). A combination of high-throughput screening and iterative medicinal chemistry optimization led to the development of the highly selective PI3KC2α inhibitors (PITCOINs) 201,210,211 . The most selective of these molecules (PITCOIN3) is exquisitely sensitive for PI3KC2α, with no inhibition of >100 other tested human lipid and protein kinases, and high selectivity over other class II PI3Ks.…”

RASA3 is a candidate gene in sickle cell disease‐associated pulmonary hypertension and pulmonary arterial hypertension

“…RASA3 is a ubiquitously expressed GTPase‐activating protein that inhibits R‐Ras and Rap1 activity. 17 , 18 , 19 , 20 , 21 Global loss of RASA3 expression in mice is embryonically lethal due to failure of vasculogenesis and severe bleeding. 22 Conditional endothelial cell‐specific knockout of RASA3 in mice recapitulates failure of vascular lumen formation and decreased vascular complexity.…”

“…RASA3 is a ubiquitously expressed GTPase‐activating protein that inhibits R‐Ras and Rap1 activity 17–21 . Global loss of RASA3 expression in mice is embryonically lethal due to failure of vasculogenesis and severe bleeding 22 .…”