br FGF FGFR pathway as predictive factor

FGF/FGFR pathway as predictive factor Several studies have identified FGFR1 amplification as the major predictive factor of response to FGFR inhibitors [26], [27]. However, in a recent study on lung cancer cell lines with ponatinib, FGFR1 mRNA and protein expression, together with FGF2 and FGF9 mRNA, were better predictive biomarkers of sensitivity than FGFR1 gene copy number [59]. These data were evaluated also in resected lung tumors. Approximately 50% of Sq-NSCLC with high FGFR1 gene copy number expressed high FGFR1 mRNA levels. At once, increased FGFR1 gene copy number included a significant fraction of Sq-NSCLC not expressing FGFR1 mRNA or protein (18%), providing evidence for considering that FGFR1 amplification could be occurred in both sensitive and resistant cell lines [59]. Furthermore, hot topics on the role of FGF/FGFR pathway as predictor of resistance to other targeted agents are emerging. FGFR signaling seems to be involved in tumor growth by an autocrine mechanism and may be considered a specific pathway of insensitivity to EGFR-TK inhibitors. FGF2 and FGF9 mRNA levels were significantly higher in gefitinib-insensitive 5ht and the use of FGF2-specific shRNAs or FGFR TK inhibitors induced cell growth arrest [43], [60], [61]. Furthermore, also FGFR2 and FGFR3 were de-repressed after gefitinib exposure, leading to a rapid mechanism of acquired resistance to EGFR-TK inhibitor [62]. A treatment with gefitinib and AZD4547 allowed to prevent the outgrowth of drug resistant cell clones, supporting the use of a combinatorial therapy to prevent or delay acquired resistance in EGFR-addicted NSCLC [63]. Another study showed that the concomitant use of FGFR-TK inhibitors (SU5402 or PD166866) and EGFR-TK inhibitors (erlotinib or lapatinib) was responsible for a markedly reduced cell proliferation over FGFR-TK inhibitor alone. Conversely, the concomitant administration of FGFR inhibitors and chemotherapeutics was detrimental [64]. Unfortunately, when this approach was applied in clinical trials it failed because of toxicity (see phase I trial, NCT01515969, combining erlotinib and dovitinib in advanced NSCLC). More recently, a potential role of FGFR3 as predictive marker for MET-targeted therapy has been reported. FGFR3 seems to be highly expressed in specific MET-amplified cells and its suppression enhanced the antiproliferative effects of a MET-monoclonal antibody, providing evidence for the presence of a specific crosstalk between FGFR and MET pathways [65]. Furthermore, a growing body of research have suggested that FGF/FGFR signaling pathway may also play a role in the resistance to anti-VEGF therapy after the evidence of high FGF2 levels in different cell models at the time of disease progression [22].
From preclinical evidences to clinical data Several preclinical data have shown that selective FGFR-TK inhibitors [26], [27], multi-TK inhibitors [38], [40], [41], [43], FGFR1-specific shRNAs [27] or FGF2-specific shRNAs [43] were capable of blocking tumor growth in different FGFR-addicted NSCLC cell lines. To block FGF/FGFR pathway, different targeted molecules have been developed: (1) monoclonal antibodies (mAbs); (2) ligand traps; (3) non-selective TK inhibitors and (4) selective TK inhibitors. Ongoing clinical trials in lung cancer are reported in Table 2.
Conclusions: open issues and future perspectives
Conflict of interest
Acknowledgement We thank Associazione Italiana per la Ricerca sul Cancro (AIRC) Milan, Italy grant IG 14214.
Introduction Fibroblast growth factor receptors originated in the common ancestor of Cnidaria and Bilateria (Rebscher et al., 2009). They control key functions in the development of all animals investigated so far like cell and tissue movement (Kadam et al., 2009, Klingseisen et al., 2009, Rottinger et al., 2008) boundary formation or branching morphogenesis (Affolter et al., 2009).