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Ref Type Journal Article
PMID (22238366)
Authors Gozgit JM, Wong MJ, Moran L, Wardwell S, Mohemmad QK, Narasimhan NI, Shakespeare WC, Wang F, Clackson T, Rivera VM
Title Ponatinib (AP24534), a multitargeted pan-FGFR inhibitor with activity in multiple FGFR-amplified or mutated cancer models.
Journal Molecular cancer therapeutics
Vol 11
Issue 3
Date 2012 Mar
URL
Abstract Text Members of the fibroblast growth factor receptor family of kinases (FGFR1-4) are dysregulated in multiple cancers. Ponatinib (AP24534) is an oral multitargeted tyrosine kinase inhibitor being explored in a pivotal phase II trial in patients with chronic myelogenous leukemia due to its potent activity against BCR-ABL. Ponatinib has also been shown to inhibit the in vitro kinase activity of all four FGFRs, prompting us to examine its potential as an FGFR inhibitor. In Ba/F3 cells engineered to express activated FGFR1-4, ponatinib potently inhibited FGFR-mediated signaling and viability with IC(50) values <40 nmol/L, with substantial selectivity over parental Ba/F3 cells. In a panel of 14 cell lines representing multiple tumor types (endometrial, bladder, gastric, breast, lung, and colon) and containing FGFRs dysregulated by a variety of mechanisms, ponatinib inhibited FGFR-mediated signaling with IC(50) values <40 nmol/L and inhibited cell growth with GI(50) (concentration needed to reduce the growth of treated cells to half that of untreated cells) values of 7 to 181 nmol/L. Daily oral dosing of ponatinib (10-30 mg/kg) to mice reduced tumor growth and inhibited signaling in all three tumor models examined. Importantly, the potency of ponatinib in these models is similar to that previously observed in BCR-ABL-driven models and plasma levels of ponatinib that exceed the IC(50) values for FGFR1-4 inhibition can be sustained in patients. These results show that ponatinib is a potent pan-FGFR inhibitor and provide strong rationale for its evaluation in patients with FGFR-driven cancers.

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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
FGFR1 amp estrogen-receptor positive breast cancer sensitive Dovitinib Preclinical Actionable In a preclinical study, Dovitinib (TKI258) inhibited cell proliferation in estrogen receptor (ER)-positive breast cancer cells harboring FGFR1 amplification in culture (PMID: 22238366). 22238366
FGFR2 amp breast cancer sensitive Ponatinib Preclinical Actionable In a preclinical study, Iclusig (ponatinib) inhibited Fgfr phosphorylation and cell proliferation in ER-negative breast cancer cells harboring FGFR2 amplification in culture (PMID: 22238366). 22238366
FGFR3 Y375C urinary bladder cancer resistant Nintedanib Preclinical Actionable In a preclinical study, bladder cancer cells harboring FGFR3 Y375C were resistant to growth inhibition by Ofev (Nintedanib) in culture (PMID: 22238366). 22238366
FGFR2 amp stomach cancer no benefit Brivanib Preclinical Actionable In a preclinical study, Brivanib (BMS-540215) did not inhibit growth of gastric cancer cells harboring FGFR2 amplification in culture (PMID: 22238366). 22238366
FGFR3 S249C urinary bladder cancer sensitive Ponatinib Preclinical - Cell line xenograft Actionable In a preclinical study, Iclusig (ponatinib) inhibited growth of bladder cancer cells harboring FGFR3 S249C in culture and in cell line xenograft models (PMID: 22238366). 22238366
FGFR2 S252W endometrial cancer sensitive Brivanib Preclinical Actionable In a preclinical study, Brivanib (BMS-540215) inhibited growth of endometrial cancer cells harboring FGFR2 S252W in culture (PMID: 22238366). 22238366
FGFR3 Y375C urinary bladder cancer no benefit Brivanib Preclinical Actionable In a preclinical study, Brivanib (BMS-540215) did not inhibit growth of bladder cancer cells harboring FGFR3 Y375C in culture (PMID: 22238366). 22238366
FGFR1 act mut Advanced Solid Tumor decreased response Nintedanib Preclinical Actionable In a preclinical study, transformed cells expressing constitutively active FGFR1 demonstrated reduced sensitivity to Ofev (Nintedanib) in culture, when compared to other tyrosine kinase inhibitors (PMID: 22238366). 22238366
FGFR1 amp lung cancer no benefit Brivanib Preclinical Actionable In a preclinical study, Brivanib (BMS-540215) did not inhibit growth of lung cancer cells with FGFR1 amplification in culture (PMID: 22238366). 22238366
FGFR2 act mut Advanced Solid Tumor decreased response Nintedanib Preclinical Actionable In a preclinical study, transformed cells expressing constitutively active FGFR2 demonstrated reduced sensitivity to Ofev (Nintedanib) in culture, when compared to other tyrosine kinase inhibitors (PMID: 22238366). 22238366
FGFR3 act mut Advanced Solid Tumor sensitive Ponatinib Preclinical Actionable In a preclinical study, Iclusig (ponatinib) inhibited receptor phosphorylation and cell growth in transformed cells expressing constitutively active FGFR3 in culture (PMID: 22238366). 22238366
FGFR2 S252W endometrial cancer sensitive Cediranib Preclinical Actionable In a preclinical study, Cediranib (AZD-2171) inhibited growth of endometrial cancer cells harboring FGFR2 S252W in culture (PMID: 22238366). 22238366
FGFR2 amp colon cancer sensitive Cediranib Preclinical Actionable In a preclinical study, Cediranib (AZD-2171) inhibited growth of colon cancer cells harboring FGFR2 amplification in culture (PMID: 22238366). 22238366
FGFR1 act mut Advanced Solid Tumor no benefit Brivanib Preclinical Actionable In a preclinical study, Brivanib (BMS-540215) did not inhibit receptor phosphorylation and cell proliferation in transformed cells expressing constitutively active FGFR1 in culture (PMID: 22238366). 22238366
FGFR2 act mut Advanced Solid Tumor sensitive Ponatinib Preclinical Actionable In a preclinical study, Iclusig (ponatinib) inhibited receptor phosphorylation and cell growth in transformed cells expressing constitutively active FGFR2 in culture (PMID: 22238366). 22238366
FGFR1 amp lung squamous cell carcinoma sensitive Ponatinib Preclinical Actionable In a preclinical study, Iclusig (ponatinib) inhibited growth of squamous cell lung cancer cell lines harboring FGFR1 amplification (PMID: 22238366). 22238366
FGFR2 S252W endometrial cancer sensitive Nintedanib Preclinical Actionable In a preclinical study, Ofev (Nintedanib) inhibited cell proliferation in endometrial cancer cells harboring FGFR2 S252W mutation in culture (PMID: 22238366). 22238366
FGFR2 S252W endometrial cancer decreased response Dovitinib Preclinical Actionable In a preclinical study, Dovitinib (TKI258) did not potently inhibit cell proliferation in endometrial cancer cells harboring FGFR2 S252W mutation in culture (PMID: 22238366). 22238366
FGFR3 Y375C urinary bladder cancer resistant Cediranib Preclinical Actionable In a preclinical study, bladder cancer cells harboring an FGFR3 Y375C mutation were resistant to growth inhibition by Cediranib (AZD-2171) in culture (PMID: 22238366). 22238366
FGFR2 wild-type breast cancer resistant Ponatinib Preclinical Actionable In a preclinical study, ER-negative breast cancer cells with wild-type FGFR2 were resistant to growth inhibition by Iclusig (ponatinib) in cell culture (PMID: 22238366). 22238366
FGFR2 N549K endometrial cancer no benefit Brivanib Preclinical Actionable In a preclinical study, Brivanib (BMS-540215) did not inhibit growth of endometrial cancer cells harboring FGFR2 N549K in cell culture (PMID: 22238366). 22238366
FGFR3 act mut Advanced Solid Tumor sensitive Dovitinib Preclinical Actionable In a preclinical study, Dovitinib (TKI258) inhibited receptor phosphorylation and cell proliferation in transformed cells expressing constitutively active FGFR3 in culture (PMID: 22238366). 22238366
FGFR3 S249C urinary bladder cancer sensitive Dovitinib Preclinical Actionable In a preclinical study, Dovitinib (TKI258) inhibited cell proliferation in bladder cancer cells harboring FGFR3 S249C mutation in culture (PMID: 22238366). 22238366
FGFR2 amp colon cancer sensitive Dovitinib Preclinical Actionable In a preclinical study, Dovitinib (TKI258) inhibited cell proliferation in colon cancer cells harboring FGFR2 amplification in culture (PMID: 22238366). 22238366
FGFR2 amp stomach cancer sensitive Dovitinib Preclinical Actionable In a preclinical study, Dovitinib (TKI258) inhibited cell proliferation in gastric cancer cell lines harboring FGFR2 amplification in culture (PMID: 22238366). 22238366
FGFR1 act mut Advanced Solid Tumor decreased response Cediranib Preclinical Actionable In a preclinical study, transformed cells expressing constitutively active FGFR1 demonstrated reduced sensitivity to inhibition of receptor phosphorylation and cell proliferation by Cediranib (AZD-2171) in culture, when compared to other tyrosine kinase inhibitors (PMID: 22238366). 22238366
FGFR2 amp colon cancer no benefit Brivanib Preclinical Actionable In a preclinical study, Brivanib (BMS-540215) did not inhibit growth of colon cancer cells harboring FGFR2 amplification in culture (PMID: 22238366). 22238366
FGFR3 Y375C urinary bladder cancer sensitive Dovitinib Preclinical Actionable In a preclinical study, Dovitinib (TKI258) inhibited cell proliferation in bladder cancer cells harboring FGFR3 Y375C in culture (PMID: 22238366). 22238366
FGFR2 wild-type colon cancer resistant Ponatinib Preclinical Actionable In a preclinical study, colon cancer cells with wild-type FGFR2 were resistant to growth inhibition by Iclusig (ponatinib) in cell culture (PMID: 22238366). 22238366
FGFR2 wild-type stomach cancer resistant Ponatinib Preclinical Actionable In a preclinical study, gastric cancer cells with wild-type FGFR2 were resistant to growth inhibition by Iclusig (ponatinib) in cell culture (PMID: 22238366). 22238366
FGFR3 Y375C urinary bladder cancer sensitive Ponatinib Preclinical Actionable In a preclinical study, Iclusig (ponatinib) inhibited Fgfr phosphorylation and cell proliferation in bladder cancer cells harboring FGFR3 Y375C in culture (PMID: 22238366). 22238366
FGFR1 amp breast cancer sensitive Ponatinib Preclinical Actionable In a preclinical study, Iclusig (ponatinib) inhibited Fgfr phosphorylation and cell proliferation in ER-positive breast cancer cells harboring FGFR1 amplification in culture (PMID: 22238366). 22238366
FGFR3 S249C urinary bladder cancer no benefit Brivanib Preclinical Actionable In a preclinical study, Brivanib (BMS-540215) did not inhibit growth of bladder cancer cells harboring FGFR3 S249C in culture (PMID: 22238366). 22238366
FGFR2 N549K endometrial cancer sensitive Cediranib Preclinical Actionable In a preclinical study, Cediranib (AZD-2171) inhibited growth of endometrial cancer cells harboring FGFR2 N549K in cell culture (PMID: 22238366). 22238366
FGFR3 S249C urinary bladder cancer resistant Nintedanib Preclinical Actionable In a preclinical study, bladder cancer cells harboring FGFR3 S249C were resistant to Ofev (Nintedanib) induced inhibition of cell proliferation in culture (PMID: 22238366). 22238366
FGFR2 act mut Advanced Solid Tumor decreased response Cediranib Preclinical Actionable In a preclinical study, transformed cells expressing constitutively active FGFR2 demonstrated reduced sensitivity to inhibition of receptor phosphorylation and cell proliferation by Cediranib (AZD-2171) in culture, when compared to other tyrosine kinase inhibitors (PMID: 22238366). 22238366
FGFR3 act mut Advanced Solid Tumor decreased response Cediranib Preclinical Actionable In a preclinical study, transformed cells expressing constitutively active FGFR3 demonstrated reduced sensitivity to inhibition of receptor phosphorylation and cell proliferation by Cediranib (AZD-2171) in culture, when compared to other tyrosine kinase inhibitors (PMID: 22238366). 22238366
FGFR2 N549K endometrial cancer sensitive Ponatinib Preclinical - Cell line xenograft Actionable In a preclinical study, Iclusig (ponatinib) inhibited growth of endometrial cancer cells harboring FGFR2 N549K in culture and in cell line xenograft models (PMID: 22238366). 22238366
FGFR2 act mut Advanced Solid Tumor sensitive Dovitinib Preclinical Actionable In a preclinical study, Dovitinib (TKI258) inhibited receptor phosphorylation and cell proliferation in transformed cells expressing constitutively active FGFR2 in culture (PMID: 22238366). 22238366
FGFR1 amp estrogen-receptor positive breast cancer sensitive Nintedanib Preclinical Actionable In a preclinical study, Ofev (nintedanib) inhibited the growth of ER-positive breast cancer cells harboring FGFR1 amplification in culture (PMID: 22238366). 22238366
FGFR1 amp estrogen-receptor positive breast cancer sensitive Cediranib Preclinical Actionable In a preclinical study, Cediranib (AZD-2171) inhibited growth of estrogen receptor (ER)-positive breast cancer cells with FGFR1 amplification in culture (PMID: 22238366). 22238366
FGFR3 act mut Advanced Solid Tumor decreased response Nintedanib Preclinical Actionable In a preclinical study, transformed cells expressing constitutively active FGFR3 demonstrated reduced sensitivity to Ofev (Nintedanib) in culture, when compared to other tyrosine kinase inhibitors (PMID: 22238366). 22238366
FGFR1 amp estrogen-receptor positive breast cancer no benefit Brivanib Preclinical Actionable In a preclinical study, Brivanib (BMS-540215) did not inhibit growth of estrogen receptor (ER)-positive breast cancer cells with FGFR2 amplification in culture (PMID: 22238366). 22238366
FGFR2 N549K endometrial cancer resistant Nintedanib Preclinical Actionable In a preclinical study, Ofev (Nintedanib) did not inhibit growth of endometrial cancer cells harboring FGFR2 N549K in cell culture (PMID: 22238366). 22238366
FGFR1 act mut Advanced Solid Tumor sensitive Ponatinib Preclinical Actionable In a preclinical study, Iclusig (ponatinib) inhibited receptor phosphorylation and cell growth in transformed cells expressing constitutively active FGFR1 in culture (PMID: 22238366). 22238366
FGFR2 act mut Advanced Solid Tumor decreased response Brivanib Preclinical Actionable In a preclinical study, transformed cells expressing constitutively active FGFR2 demonstrated reduced sensitivity to inhibition of receptor phosphorylation and cell proliferation by Brivanib (BMS-540215) in culture, when compared to other tyrosine kinase inhibitors (PMID: 22238366). 22238366
FGFR2 amp colon cancer sensitive Nintedanib Preclinical Actionable In a preclinical study, Ofev (nintedanib) inhibited growth of colon cancer cells harboring FGFR2 amplification in culture (PMID: 22238366). 22238366
FGFR3 wild-type urinary bladder cancer resistant Ponatinib Preclinical Actionable In a preclinical study, bladder cancer cells with wild-type FGFR3 were resistant to growth inhibition by Iclusig (ponatinib) in cell culture (PMID: 22238366). 22238366
FGFR1 wild-type breast cancer resistant Ponatinib Preclinical Actionable In a preclinical study, ER-positive breast cancer cells with wild-type FGFR1 were resistant to growth inhibition by Iclusig (ponatinib) in cell culture (PMID: 22238366). 22238366
FGFR2 amp colon cancer sensitive Ponatinib Preclinical Actionable In a preclinical study, Iclusig (ponatinib) inhibited Fgfr phosphorylation and cell proliferation in colon cancer cells harboring FGFR2 amplification in culture (PMID: 22238366). 22238366
FGFR1 act mut Advanced Solid Tumor sensitive Dovitinib Preclinical Actionable In a preclinical study, Dovitinib (TKI258) inhibited receptor phosphorylation and cell proliferation in transformed cells expressing constitutively active FGFR1 in culture (PMID: 22238366). 22238366
FGFR2 wild-type endometrial cancer resistant Ponatinib Preclinical Actionable In a preclinical study, endometrial cancer cells with wild-type FGFR2 were resistant to growth inhibition by Iclusig (ponatinib) in cell culture (PMID: 22238366). 22238366
FGFR2 amp stomach cancer sensitive Cediranib Preclinical Actionable In a preclinical study, Cediranib (AZD-2171) inhibited growth of gastric cancer cells harboring FGFR2 amplification in culture (PMID: 22238366). 22238366
FGFR2 N549K endometrial cancer decreased response Dovitinib Preclinical Actionable In a preclinical study, Dovitinib (TKI258) did not potently inhibit proliferation of endometrial cancer cell lines harboring FGFR2 N549K in cell culture (PMID: 22238366). 22238366
FGFR2 S252W endometrial cancer sensitive Ponatinib Preclinical Actionable In a preclinical study, Iclusig (ponatinib) inhibited Fgfr2 phosphorylation and cell proliferation in endometrial cancer cells harboring FGFR2 S252W in culture (PMID: 22238366). 22238366
FGFR2 amp estrogen-receptor negative breast cancer no benefit Brivanib Preclinical Actionable In a preclinical study, Brivanib (BMS-540215) did not inhibit growth of estrogen receptor (ER)-negative breast cancer cells with FGFR2 amplification in culture (PMID: 22238366). 22238366
FGFR3 S249C urinary bladder cancer sensitive Cediranib Preclinical Actionable In a preclinical study, Cediranib (AZD-2171) inhibited growth of bladder cancer cells harboring FGFR3 S249C mutation in culture (PMID: 22238366). 22238366
FGFR2 amp stomach cancer sensitive Ponatinib Preclinical - Cell line xenograft Actionable In a preclinical study, Iclusig (ponatinib) inhibited proliferation of FGFR2-amplified gastric cancer cells in culture, and inhibited tumor growth in FGFR2-amplified gastric cancer cell line xenograft models (PMID: 22238366). 22238366
FGFR3 act mut Advanced Solid Tumor no benefit Brivanib Preclinical Actionable In a preclinical study, Brivanib (BMS-540215) did not inhibit receptor phosphorylation and cell proliferation in transformed cells expressing constitutively active FGFR3 in culture (PMID: 22238366). 22238366