Inhibition of Ron Kinase Blocks Conversion of Micrometastases to Overt Metastases by Boosting Antitumor Immunity

Abstract

Many “non-metastatic” cancers have spawned undetectable metastases prior to diagnosis. Eventual outgrowth of these microscopic lesions causes metastatic relapse and death, yet the events that dictate when and how micrometastases convert to overt metastases are largely unknown. We report that macrophage stimulating protein (MSP) and its receptor, Ron, are key mediators in conversion of micrometastases to bona fide metastatic lesions through immune suppression. Genetic deletion of Ron tyrosine kinase activity specifically in the host profoundly blocked metastasis. Our data show that loss of Ron function promotes an effective anti-tumor CD8+ T cell response, which specifically inhibits outgrowth of seeded metastatic colonies. Treatment of mice with a Ron-selective kinase inhibitor prevented outgrowth of lung metastasis, even when administered after micrometastatic colonies had already been established. Our findings indicate that Ron inhibitors may hold potential to specifically prevent outgrowth of micrometastases in cancer patients in the adjuvant setting.

Inhibition of RON kinase potentiates anti-CTLA-4 immunotherapy to shrink breast tumors and prevent metastatic outgrowth

“…Rather, it activates a complex immunomodulatory gene expression signature that ultimately suppresses CD8 + T cell activity to facilitate tumor progression and metastasis. 31,34,35 …”

“…34 The ability of RON signaling to upregulate CD80 and PD-L1, amongst a large collection of other immunosuppressive molecules, led us to hypothesize that inhibition of RON might cooperate with approved checkpoint inhibitors such as anti-CTLA-4 (aCTLA-4) and anti-PD-1(aPD-1) to enhance anti-tumor responses. We utilized our previously described MMTV-PyMT model 16,34 to investigate this question.…”

“…29–33 Previously, we and others have shown that host RON signaling negatively regulates antitumor immunity in mouse models of cancer. 31,34,35 Importantly, host RON was critical for conversion of micrometastatic lesions into overt clinical metastases, a step that is thought to be rate-limiting in the deadly metastatic cascade. 34 Inhibition of RON activity with a MET/RON dual kinase inhibitor BMS777607 (also known as ASLAN002) 36 also blocked metastatic outgrowth in a manner that was dependent on CD8 + T cells.…”

“…31,34,35 Importantly, host RON was critical for conversion of micrometastatic lesions into overt clinical metastases, a step that is thought to be rate-limiting in the deadly metastatic cascade. 34 Inhibition of RON activity with a MET/RON dual kinase inhibitor BMS777607 (also known as ASLAN002) 36 also blocked metastatic outgrowth in a manner that was dependent on CD8 + T cells. 34 BMS777607/ASLAN002 has been in clinical trials and exhibited a good tolerability profile and demonstrated biological effects on RON-mediated activities.…”

“…34 Inhibition of RON activity with a MET/RON dual kinase inhibitor BMS777607 (also known as ASLAN002) 36 also blocked metastatic outgrowth in a manner that was dependent on CD8 + T cells. 34 BMS777607/ASLAN002 has been in clinical trials and exhibited a good tolerability profile and demonstrated biological effects on RON-mediated activities. 37–39 …”