Article Figures & Data
Figures
- Figure 1.
The FGFR structure and signaling network. FGFRs are single-pass transmembrane receptors with an extracellular domain comprising 3 Ig-like domains (Ig-I–III) and an intracellular tyrosine kinase domain. The ligand-receptor binding is stabilized by the interaction with HPSG, thus inducing receptor dimerization and transphosphorylation at several tyrosine residues in the intracellular portion of FGFR. Two main downstream pathways are shown. The first induces Ras-dependent MAPK signaling, and the second leads to PI3K/Akt activation, independently and in parallel with Ras. PLC-γ may also be activated, thus triggering PKC, which converges with the MAPK pathway. Other pathways may be switched on, such as the STAT-dependent pathway. Many negative regulators are able to attenuate signaling at different levels, including FGFRL1, SEF, SPRY, and MAPK phosphatase 1 and 3 (MKP1 and MKP3) MEK, MAP-ERK kinase.
- Figure 2.
Challenges and open questions in anti-FGFR drug development.
Tables
- Table 1.
Activating genetic alterations in FGFR and related cancer types
Gene Alteration Cancer type (incidence, if known; reference) FGFR1 Amplification Squamous NSCLC (20%; ref. 9) Breast cancer (10%; ref. 10) Ovarian cancer (∼5%; ref. 11) Bladder cancer (3%; ref. 12) Others: oral squamous cell carcinoma, esophageal squamous carcinoma, prostate cancer (13–15) Mutation Melanoma (rare), glioblastoma (16, 17) Translocation 8p11 myeloproliferative syndrome, chronic myeloid leukemia (rare; refs. 18, 19) FGFR2 Amplification Gastric cancer (10%; ref. 20) Breast cancer (4% of triple-negative cases; ref. 21) Mutation Endometrial cancer (12%; ref. 22) Squamous NSLC (5%; ref. 8) Gastric cancer (rare; ref. 23) Germline SNP Second intron SNP: breast cancer susceptibility (24) FGFR3 Amplification Bladder cancer (25) Salivary adenoid cystic cancer (26) Mutation Bladder cancer (50–60% non-muscle invasive; 10–15% muscle invasive; ref. 27) Cervical cancer (5%; ref. 28) Myeloma (5% of the translocated cases; ref. 29) Prostate cancer (3%; ref. 30) Spermatocytic seminoma (7%; ref. 31) Colorectal cancer (23) Oral squamous cancer (32) Translocation Myeloma (15%-20%; ref. 33) Peripheral T-cell lymphoma (rare; ref. 34) FGFR4 Mutation Rhabdomyosarcoma (7%-8%; ref. 35) Germline SNP Coding SNP: poor prognosis in many cancer types (36) - Table 2.
Ongoing clinical evaluation of anti-FGFR drugs with IC50< 100 nmol against at least one FGFR
Targets and IC50, nmol/L (if available) Compound FGFR1 FGFR2 FGFR3 FGFR4 VEGFR1 VEGFR2 VEGFR3 PDGFR-α PDGFR-β Others [IC50, nmol/L] Clinical development Company MultitargetedTKIs TKI258 (dovitinib; ref. 64) 8 9 10 13 8 200 27 FLT-3 [1] Phase III (RCC) Novartis KIT [2] CSF-1 [36] BIBF1120 (nintedanib; ref. 65) 69 37 108 610 34 21 13 59 65 LCK [16] Phase III (NSCLC, ovarian) Boehringer-Ingelheim FLT-3 [26] SRC [156] LYN [195] E3810 (66) 17.5 82.5 237.5 >1,000 7 25 10 175 525 CSF-1 [5] Phase 1 (solid tumors) Ethical Oncology of Science KIT [456] E7080 (lenvat-inib; ref. 67) 46 22 4 5.2 51 39 KIT [100] Phase III (thyroid) Eisai BMS582664 (brivanib; ref. 68) 148 125 68 380 25 10 >6,000 Phase III (HCC, CRC) Bristol-Myers Squibb ENMD-2076 (69) 93 71 500 58 16 56.4 FLT-3 [2] Phase II (breast, ovarian) Entremed RET [10.4] SRC [20.2] CSF-1 [24.8] Aurora A [14] Aurora B [350] KIT [120] TSU68 (orantinib; ref. 70) 1.2μmol/L 2.1 μmol/L 0.008 μmol/L Phase III (HCC) Taiho Pharmaceutical AP24534 (ponatinib; ref. 71) 2 2 18 8 1.5 1.1 ABL [0.7] Phase II (ALL, CML) Ariad SRC [5.4] LYN [0.24] KIT [12.5] Selective TKIs AZD4547 (72) 0.2 2.5 1.8 165 24 IGFR [581] Phase II (breast, gastric) AstraZeneca BGJ398 (73) 0.9 1.4 1 60 Phase 1 (solid tumors) Novartis LY2874455 (74) 2.8 2.6 6.4 6 7a Phase 1 (solid tumors) Eli Lilly Monoclonal antibodies MGFR1877S [cl in icalt rials.gov] Phase I (MM, solid tumors) Genentech FGF traps HGS1036/FP-1039(75) FGF1 Phase I (solid tumors) Human Genomic Sciences FGF2 FGF4 aSix- to 9-fold cellular and in vivo selectivity on inhibition of FGF- over VEGF-mediated target signaling in mice.
Abbreviations: ALL, acute lymphoblastic leukemia: CML, chronic myeloid leukemia: CRC, colorectal cancer: FLT-3, Fms-like tyrosine kinase receptor 3: HCC, hepatocellular carcinoma: IGFR, insulin-like growth factor receptor: MM, multiple myeloma: RCC, renal cell carcinoma: STS, soft tissue sarcoma.
Volume 3, Issue 3
