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Ref Type Journal Article
PMID (26289070)
Authors Bieniasz M, Radhakrishnan P, Faham N, De La O JP, Welm AL
Title Preclinical Efficacy of Ron Kinase Inhibitors Alone and in Combination with PI3K Inhibitors for Treatment of sfRon-Expressing Breast Cancer Patient-Derived Xenografts.
Journal Vol Issue Date Pages Journal Short Title
Clinical cancer research : an official journal of the American Association for Cancer Research 21 24 2015 Dec 15 5588-600 Clin Cancer Res
URL
Abstract Text 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 antitumor effects of Ron kinase inhibitor therapy while also preventing potential therapeutic resistance to tyrosine kinase inhibitors (TKI).We used patient-derived breast tumor xenografts (PDX) as high-fidelity preclinical models to determine the efficacy of single-agent or dual Ron/PI3K inhibition. We tested the Ron kinase inhibitor ASLAN002 with and without coadministration of the PI3K inhibitor NVP-BKM120 in hormone receptor-positive [estrogen receptor (ER)(+)/progesterone receptor (PR)(+)] breast PDXs with and without PIK3CA gene mutation.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.Our work provides preclinical rationale for targeting sfRon in patients with breast cancer, 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. Clin Cancer Res; 21(24); 5588-600. ©2015 AACR.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
MST1R pos PIK3CA H1047R estrogen-receptor positive breast cancer predicted - sensitive Buparlisib Preclinical - Pdx Actionable In a preclinical study, BKM120 inhibited tumor growth in patient-derived xenograft (PDX) models of estrogen-receptor positive breast cancer harboring PIK3CA H1047R and expressing the short isoform of MST1R (RON) (PMID: 26289070). 26289070
MST1R pos PIK3CA wild-type estrogen-receptor positive breast cancer predicted - sensitive BMS-777607 Preclinical - Pdx Actionable In a preclinical study, BMS-777607 (ASLAN002) inhibited tumor growth in patient-derived xenograft (PDX) models of estrogen-receptor positive breast cancer with wild-type PIK3CA and expressing the short isoform of MST1R (RON) (PMID: 26289070). 26289070
MST1R act mut breast cancer predicted - sensitive BMS-777607 + Buparlisib Preclinical - Cell line xenograft Actionable In a preclinical study, the combination of BKM120 and BMS-777607 (ASLAN002) inhibited tumor growth in breast cancer cell line xenograft models expressing a constitutively active short isoform of MST1R (RON), with increased efficacy over either agent alone (PMID: 26289070). 26289070
MST1R act mut breast cancer predicted - sensitive BMS-777607 Preclinical - Cell line xenograft Actionable In a preclinical study, BMS-777607 (ASLAN002) inhibited tumor growth in breast cancer cell line xenograft models expressing a constitutively active short isoform of MST1R (RON) (PMID: 26289070). 26289070
MST1R pos PIK3CA E545K breast cancer predicted - sensitive Buparlisib Preclinical - Cell culture Actionable In a preclinical study, BKM120 decreased viability of a breast cancer cell line expressing the constitutively active short isoform of MST1R (RON) and PIK3CA E545K in culture (PMID: 26289070). 26289070
MST1R pos PIK3CA E545K breast cancer predicted - sensitive BMS-777607 Preclinical - Cell culture Actionable In a preclinical study, BMS-777607 decreased viability of a breast cancer cell line expressing the constitutively active short isoform of MST1R (RON) and PIK3CA E545K in culture (PMID: 26289070). 26289070
MST1R pos PIK3CA H1047R estrogen-receptor positive breast cancer predicted - sensitive BMS-777607 + Buparlisib Preclinical - Pdx Actionable In a preclinical study, the combination of BKM120 and BMS-777607 (ASLAN002) inhibited tumor growth in patient-derived xenograft (PDX) models of estrogen-receptor positive breast cancer harboring PIK3CA H1047R and expressing the short isoform of MST1R (RON) (PMID: 26289070). 26289070
MST1R pos PIK3CA wild-type estrogen-receptor positive breast cancer predicted - sensitive Buparlisib Preclinical - Pdx Actionable In a preclinical study, BKM120 inhibited tumor growth in patient-derived xenograft (PDX) models of estrogen-receptor positive breast cancer with wild-type PIK3CA and expressing the short isoform of MST1R (RON) (PMID: 26289070). 26289070
MST1R pos PIK3CA wild-type estrogen-receptor positive breast cancer predicted - sensitive BMS-777607 + Buparlisib Preclinical - Pdx Actionable In a preclinical study, the combination of BKM120 and BMS-777607 (ASLAN002) inhibited tumor growth in patient-derived xenograft (PDX) models of estrogen-receptor positive breast cancer with wild-type PIK3CA and expressing the short isoform of MST1R (RON) (PMID: 26289070). 26289070
MST1R pos PIK3CA H1047R estrogen-receptor positive breast cancer predicted - sensitive BMS-777607 Preclinical - Pdx Actionable In a preclinical study, BMS-777607 (ASLAN002) inhibited tumor growth in patient-derived xenograft (PDX) models of estrogen-receptor positive breast cancer harboring PIK3CA H1047R and expressing the short isoform of MST1R (RON) (PMID: 26289070). 26289070
MST1R act mut breast cancer predicted - sensitive OSI-296 Preclinical - Cell line xenograft Actionable In a preclinical study, OSI-296 inhibited tumor growth in breast cancer cell line xenograft models expressing a constitutively active short isoform of MST1R (RON) (PMID: 26289070). 26289070