Preclinical Efficacy of Ron Kinase Inhibitors Alone and in Combination with PI3K Inhibitors for Treatment of sfRon-Expressing Breast Cancer Patient-Derived Xenografts

Abstract

Purpose Recent studies have demonstrated that short-form Ron (sfRon) kinase drives breast tumor progression and metastasis through robust activation of the PI3K pathway. We reasoned that upfront, concurrent inhibition of sfRon and PI3K might enhance the anti-tumor effects of Ron kinase inhibitor therapy while also preventing potential therapeutic resistance to tyrosine kinase inhibitors (TKIs). Experimental design We used patient-derived breast tumor xenografts (PDXs) as high-fidelity pre-clinical models to determine the efficacy of single agent or dual Ron/PI3K inhibition. We tested the Ron kinase inhibitor ASLAN002 with and without co-administration of the PI3K inhibitor NVP-BKM120 in hormone receptor positive (ER+/PR+) breast PDXs with and without PIK3CA gene mutation. Results Breast PDX tumors harboring wild-type PIK3CA showed a robust response to ASLAN002 as a single agent. In contrast, PDX tumors harboring mutated PIK3CA demonstrated partial resistance to ASLAN002, which was overcome with addition of NVP-BKM120 to the treatment regimen. We further demonstrated that concurrent inhibition of sfRon and PI3K in breast PDX tumors with wild-type PIK3CA provided durable tumor stasis after therapy cessation, whereas discontinuation of either monotherapy facilitated tumor recurrence. Conclusion Our work provides pre-clinical rationale for targeting sfRon in breast cancer patients, with the important stipulation that tumors harboring PIK3CA mutations may be partially resistant to Ron inhibitor therapy. Our data also indicate that tumors with wild type PIK3CA are most effectively treated with an upfront combination of Ron and PI3K inhibitors for the most durable response.

Short-form Ron is a novel determinant of ovarian cancer initiation and progression

“…Our previous work revealed that sfRon is an important contributor to breast cancer pathogenesis [ 3 , 8 ]. To complement our studies focused on the role of sfRon in breast tumor progression and metastasis, we investigated the requirement for endogenous sfRon in the initiation of breast and other cancers.…”

Progress in tumor-associated macrophage (TAM)-targeted therapeutics

“…Alternatively, restoration of iNOS expression in MSP-stimulated macrophages may be achieved via inhibition of PI3k, one of the downstream targets of RON activation [83]. In fact, a synergistic therapeutic effect between the RON kinase inhibitor and a PI3k inhibitor NVP-BKM120 has been reported in a mouse xenograft model of patient-derived breast tumor where cancer cells express constitutively active isoform of RON (short-form RON or sfRON) [86]. Both RON and PI3k inhibitors are being investigated in clinical trials [85][87].…”

RON Signaling Is a Key Mediator of Tumor Progression in Many Human Cancers

“…To our knowledge, BMS-777607 and LCRF-0004 are the only SMIs reported to inhibit RON at lower IC 50 than Met (Schroeder et al 2009;Raeppel et al 2010Raeppel et al , 2015. BMS-777607/ASLAN002 has shown very promising results in preclinical models of breast, pancreatic, prostate, and colorectal cancer and has recently finished phase I clinical trials (Dai and Siemann 2010;Eyob et al 2013a;Zeng et al 2014;Bieniasz et al 2015;Andrade et al 2017). However, as experienced with other single targeted therapies (Alexander and Wang 2015), resistance has been reported with targeting RON alone, even in cancers that were highly addicted to RON signaling (Sharma et al 2013;Zhao et al 2013;Kang et al 2014).…”

“…Monoclonal antibodies have shown efficacy in some preclinical models (O'Toole et al 2006;Li et al 2010;Padhye et al 2011;Yao et al 2011). However, SMIs might have potential to be used in a more widespread way, given that RON activity does not always depend on MSP (Yao et al 2013a;Bieniasz et al 2015). Likewise, it is unclear how anti-RON antibodies might affect signaling when another RTK is involved.…”