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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. | ||||||||||||
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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 | Indication/Tumor Type | Response Type | Therapy Name | Approval Status | Evidence Type | Efficacy Evidence | References |
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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 |
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 |
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 |
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 |
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 |
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 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 |
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 |
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 |
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 |
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 |
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 |
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 |
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 |
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 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 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 |
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 |
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 |
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 |
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 |
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 |
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 |
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 |
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 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 |
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 | 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 |
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 |
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 |
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 |
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 |
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 |
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 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 | 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 |
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 |
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 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 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 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 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 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 |
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 |
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 |
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 |
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 |
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 |
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 |
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 |
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 |
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 |
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 |
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 |
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 |
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 |
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