Br J Cancer: RON promotes therapeutic resistance to ESR1 mutant breast cancer

Globally, more than 600,000 women die each year from metastasis breast cancer (MBC).
Although effective endocrine therapy and targeted therapy can be used for the treatment of estrogen-positive breast cancer (BC), 20% of women still experience cancer recurrence and/or metastasis.
ER-positive MPC patients often experience ESR1 (estrogen recipient 1) mutations after receiving AI (aromatase inhibitors) in a metastasis environment.
mutation is also the most common mechanism of endocrine therapy (ET) resistance, characterized by transcriptional activity with hormone hypersensitism or lien dependence.
study schematic obtained ESR1 mutation corresponds to a patient's poor prognostication and lacks an effective strategy for the treatment of these cancers.
, identifying potential therapeutic targets in ESR1 mutant cancers is necessary to better control metastasis.
researchers identified ultra-active kinases in ESR1 mutant cells by conducting proteomic analysis in ESR1 Y537S mutant cells.
, RON and PI3K were found to be highly active through phosphate immunoprinting experiments, organ-like growth experiments, and human-source transplant tumor (PDX) metastasis models.
ESR1 mutation model showed non-dependent growth and metastasis tendencies of estrogen, and researchers found that RON was over-activated in the ESR1 mutation model and in the obtained Palbociclib model.
pharmacological and genetic inhibition results showed that RON was able to interact with IGF-1R (insulin-like growth factor 1 subject) and be regulated by mutant ER, as evidenced by reduced expression levels of endocrine therapy (ET) phosphorylation proteins.
combination of RONi and ET can reduce the growth of ESR1 mutant organs and demonstrate therapeutic efficacy as a single therapy in the PalbR model.
treatment of ET and RONi can significantly reduce the transfer of ESR1 Y537S mutant PDX models.
inhibitor RON signaling path can restore ET sensitivity, the results show that inhibition of RON/PI3K paths may be a potentially effective treatment strategy for patients with ESR1 mutants and PalbR MBC.
and clinical data predict that ET's drug resistance mechanism may also lead to resistance to CDK4/6 inhibitors.
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