1932

Abstract

Biliary tract cancer (BTC) is the second most common primary liver cancer after hepatocellular carcinoma and accounts for 2% of cancer-related deaths. BTCs are classified according to their anatomical origin into intrahepatic (iCCA), perihilar, or distal cholangiocarcinoma, as well as gall bladder carcinoma. While the mutational profiles in these anatomical BTC subtypes overlap to a large extent, iCCA is notable for the high frequency of IDH1/2 mutations (10–22%) and the nearly exclusive occurrence of FGFR2 fusions in 10–15% of patients. In recent years, FGFR2 fusions have become one of the most promising targets for precision oncology targeting BTC, with FGFR inhibitors already approved in Europe and the United States for patients with advanced, pretreated iCCA. While the therapeutic potential of nonfusion alterations is still under debate, it is expected that the field of FGFR2-directed therapies will be subject to rapid further evolution and optimization. The scope of this review is to provide an overview of oncogenic FGFR signaling in iCCA cells and highlight the pathophysiology, diagnostic testing strategies, and therapeutic promises and challenges associated with FGFR2-altered iCCA.

Loading

Article metrics loading...

/content/journals/10.1146/annurev-med-042921-024707
2023-01-27
2024-04-14
Loading full text...

Full text loading...

/deliver/fulltext/med/74/1/annurev-med-042921-024707.html?itemId=/content/journals/10.1146/annurev-med-042921-024707&mimeType=html&fmt=ahah

Literature Cited

  1. 1.
    Marin JJG, Prete MG, Lamarca A et al. 2020. Current and novel therapeutic opportunities for systemic therapy in biliary cancer. Br. J. Cancer 123:1047–59
    [Google Scholar]
  2. 2.
    Wu YM, Su F, Kalyana-Sundaram S et al. 2013. Identification of targetable FGFR gene fusions in diverse cancers. Cancer Discov. 3:636–47
    [Google Scholar]
  3. 3.
    Arai Y, Totoki Y, Hosoda F et al. 2014. Fibroblast growth factor receptor 2 tyrosine kinase fusions define a unique molecular subtype of cholangiocarcinoma. Hepatology 59:1427–34
    [Google Scholar]
  4. 4.
    Ornitz DM, Itoh N. 2015. The Fibroblast Growth Factor signaling pathway. Wiley Interdiscip. Rev. Dev. Biol. 4:215–66
    [Google Scholar]
  5. 5.
    Chen H, Ma J, Li W et al. 2007. A molecular brake in the kinase hinge region regulates the activity of receptor tyrosine kinases. Mol. Cell 27:717–30
    [Google Scholar]
  6. 6.
    Chen L, Marsiglia WM, Chen H et al. 2020. Molecular basis for receptor tyrosine kinase A-loop tyrosine transphosphorylation. Nat. Chem. Biol. 16:267–77
    [Google Scholar]
  7. 7.
    Babina IS, Turner NC. 2017. Advances and challenges in targeting FGFR signalling in cancer. Nat. Rev. Cancer 17:318–32
    [Google Scholar]
  8. 8.
    Lamberti D, Cristinziano G, Porru M et al. 2019. HSP90 inhibition drives degradation of FGFR2 fusion proteins: implications for treatment of cholangiocarcinoma. Hepatology 69:131–42
    [Google Scholar]
  9. 9.
    Cleary JM, Raghavan S, Wu Q et al. 2021. FGFR2 extracellular domain in-frame deletions are therapeutically targetable genomic alterations that function as oncogenic drivers in cholangiocarcinoma. Cancer Discov. 11:2488–505
    [Google Scholar]
  10. 10.
    Szybowska P, Kostas M, Wesche J et al. 2019. Cancer mutations in FGFR2 prevent a negative feedback loop mediated by the ERK1/2 pathway. Cells 8:518
    [Google Scholar]
  11. 11.
    Lin CC, Melo FA, Ghosh R et al. 2012. Inhibition of basal FGF receptor signaling by dimeric Grb2. Cell 149:1514–24
    [Google Scholar]
  12. 12.
    Ahmed Z, Lin CC, Suen KM et al. 2013. Grb2 controls phosphorylation of FGFR2 by inhibiting receptor kinase and Shp2 phosphatase activity. J. Cell Biol. 200:493–504
    [Google Scholar]
  13. 13.
    Tulpule A, Guan J, Neel DS et al. 2021. Kinase-mediated RAS signaling via membraneless cytoplasmic protein granules. Cell 184:2649–64.e18
    [Google Scholar]
  14. 14.
    Banani SF, Lee HO, Hyman AA, Rosen MK. 2017. Biomolecular condensates: organizers of cellular biochemistry. Nat. Rev. Mol. Cell Biol. 18:285–98
    [Google Scholar]
  15. 15.
    Lin CC, Suen KM, Jeffrey PA et al. 2022. Receptor tyrosine kinases regulate signal transduction through a liquid-liquid phase separated state. Mol. Cell 82:1089–106.e12
    [Google Scholar]
  16. 16.
    Robertson SC, Meyer AN, Hart KC et al. 1998. Activating mutations in the extracellular domain of the fibroblast growth factor receptor 2 function by disruption of the disulfide bond in the third immunoglobulin-like domain. PNAS 95:4567–72
    [Google Scholar]
  17. 17.
    Silverman IM, Hollebecque A, Friboulet L et al. 2021. Clinicogenomic analysis of FGFR2-rearranged cholangiocarcinoma identifies correlates of response and mechanisms of resistance to pemigatinib. Cancer Discov. 11:326–39
    [Google Scholar]
  18. 18.
    Meric-Bernstam F, Bahleda R, Hierro C et al. 2021. Futibatinib, an irreversible FGFR1–4 inhibitor, in patients with advanced solid tumors harboring FGF/FGFR aberrations: a phase I dose-expansion study. Cancer Discov. 12:402–15
    [Google Scholar]
  19. 19.
    Brewer JR, Mazot P, Soriano P. 2016. Genetic insights into the mechanisms of Fgf signaling. Genes Dev. 30:751–71
    [Google Scholar]
  20. 20.
    Kendre G, Marhenke S, Lorz G et al. 2021. The co-mutational spectrum determines the therapeutic response in murine FGFR2 fusion-driven cholangiocarcinoma. Hepatology 74:1357–70
    [Google Scholar]
  21. 21.
    Cristinziano G, Porru M, Lamberti D et al. 2021. FGFR2 fusion proteins drive oncogenic transformation of mouse liver organoids towards cholangiocarcinoma. J. Hepatol. 75:351–62
    [Google Scholar]
  22. 22.
    Lake D, Correa SA, Muller J. 2016. Negative feedback regulation of the ERK1/2 MAPK pathway. Cell Mol. Life Sci. 73:4397–413
    [Google Scholar]
  23. 23.
    Anastasi S, Lamberti D, Alema S, Segatto O. 2016. Regulation of the ErbB network by the MIG6 feedback loop in physiology, tumor suppression and responses to oncogene-targeted therapeutics. Semin. Cell Dev. Biol. 50:115–24
    [Google Scholar]
  24. 24.
    Lito P, Pratilas CA, Joseph EW et al. 2012. Relief of profound feedback inhibition of mitogenic signaling by RAF inhibitors attenuates their activity in BRAFV600E melanomas. Cancer Cell 22:668–82
    [Google Scholar]
  25. 25.
    Wu Q, Zhen Y, Shi L et al. 2022. EGFR inhibition potentiates FGFR inhibitor therapy and overcomes resistance in FGFR2 fusion–positive cholangiocarcinoma. Cancer Discov. 12:1378–95
    [Google Scholar]
  26. 26.
    Saborowski A, Vogel A, Segatto O. 2022. Combination therapies for targeting FGFR2 fusions in cholangiocarcinoma. Trends Cancer 8:83–86
    [Google Scholar]
  27. 27.
    Wang Y, Ding X, Wang S et al. 2016. Antitumor effect of FGFR inhibitors on a novel cholangiocarcinoma patient derived xenograft mouse model endogenously expressing an FGFR2-CCDC6 fusion protein. Cancer Lett. 380:163–73
    [Google Scholar]
  28. 28.
    Gurlevik E, Fleischmann-Mundt B, Armbrecht N et al. 2013. Adjuvant gemcitabine therapy improves survival in a locally induced, R0-resectable model of metastatic intrahepatic cholangiocarcinoma. Hepatology 58:1031–41
    [Google Scholar]
  29. 29.
    Seehawer M, Heinzmann F, D'Artista L et al. 2018. Necroptosis microenvironment directs lineage commitment in liver cancer. Nature 562:69–75
    [Google Scholar]
  30. 30.
    Saborowski A, Wolff K, Spielberg S et al. 2019. Murine liver organoids as a genetically flexible system to study liver cancer in vivo and in vitro. Hepatol. Commun. 3:423–36
    [Google Scholar]
  31. 31.
    de Jong IEM, van den Heuvel MC, Wells RG, Porte RJ. 2021. The heterogeneity of the biliary tree. J. Hepatol. 75:1236–38
    [Google Scholar]
  32. 32.
    Heiskanen M, Kononen J, Barlund M et al. 2001. CGH, cDNA and tissue microarray analyses implicate FGFR2 amplification in a small subset of breast tumors. Anal. Cell Pathol. 22:229–34
    [Google Scholar]
  33. 33.
    Turner N, Lambros MB, Horlings HM et al. 2010. Integrative molecular profiling of triple negative breast cancers identifies amplicon drivers and potential therapeutic targets. Oncogene 29:2013–23
    [Google Scholar]
  34. 34.
    Carter JH, Cottrell CE, McNulty SN et al. 2017. FGFR2 amplification in colorectal adenocarcinoma. Cold Spring Harb. Mol. Case Stud. 3:a001495
    [Google Scholar]
  35. 35.
    Helsten T, Elkin S, Arthur E et al. 2016. The FGFR landscape in cancer: analysis of 4,853 tumors by next-generation sequencing. Clin. Cancer Res. 22:259–67
    [Google Scholar]
  36. 36.
    Greenman C, Stephens P, Smith R et al. 2007. Patterns of somatic mutation in human cancer genomes. Nature 446:153–58
    [Google Scholar]
  37. 37.
    Javle M, Roychowdhury S, Kelley RK et al. 2021. Infigratinib (BGJ398) in previously treated patients with advanced or metastatic cholangiocarcinoma with FGFR2 fusions or rearrangements: mature results from a multicentre, open-label, single-arm, phase 2 study. Lancet Gastroenterol. Hepatol. 6:803–15
    [Google Scholar]
  38. 38.
    Abou-Alfa GK, Sahai V, Hollebecque A et al. 2020. Pemigatinib for previously treated, locally advanced or metastatic cholangiocarcinoma: a multicentre, open-label, phase 2 study. Lancet Oncol. 21:671–84
    [Google Scholar]
  39. 39.
    Goyal L, Meric-Bernstam F, Hollebecque A et al. 2021. Abstract CT010: Primary results of phase 2 FOENIX-CCA2: the irreversible FGFR1–4 inhibitor futibatinib in intrahepatic cholangiocarcinoma (iCCA) with FGFR2 fusions/rearrangements. Cancer Res. 81:CT010–CT
    [Google Scholar]
  40. 40.
    Mazzaferro V, El-Rayes BF, Droz Dit Busset M et al. 2019. Derazantinib (ARQ 087) in advanced or inoperable FGFR2 gene fusion-positive intrahepatic cholangiocarcinoma. Br. J. Cancer 120:165–71
    [Google Scholar]
  41. 41.
    Bekaii-Saab TS, Valle JW, Cutsem EV et al. 2020. FIGHT-302: first-line pemigatinib versus gemcitabine plus cisplatin for advanced cholangiocarcinoma with FGFR2 rearrangements. Future Oncol 16:2385–99
    [Google Scholar]
  42. 42.
    Javle MM, Borbath I, Clarke SJ et al. 2019. Infigratinib versus gemcitabine plus cisplatin multicenter, open-label, randomized, phase 3 study in patients with advanced cholangiocarcinoma with FGFR2 gene fusions/translocations: the PROOF trial. J. Clin. Oncol. 37:TPS4155-TPS
    [Google Scholar]
  43. 43.
    Borad MJ, Bridgewater JA, Morizane C et al. 2020. A phase III study of futibatinib (TAS-120) versus gemcitabine-cisplatin (gem-cis) chemotherapy as first-line (1L) treatment for patients (pts) with advanced (adv) cholangiocarcinoma (CCA) harboring fibroblast growth factor receptor 2 (FGFR2) gene rearrangements (FOENIX-CCA3). J. Clin. Oncol. 38:TPS600–TPS
    [Google Scholar]
  44. 44.
    Javle MM, Abou-Alfa GK, Macarulla T et al. 2022. Efficacy of derazantinib in intrahepatic cholangiocarcinoma patients with FGFR2 mutations or amplifications: interim results from the phase 2 study FIDES-01. J. Clin. Oncol. 40:427
    [Google Scholar]
  45. 45.
    Schram AM, Kamath SD, El-Khoueiry AB et al. 2021. First-in-human study of highly selective FGFR2 inhibitor, RLY-4008, in patients with intrahepatic cholangiocarcinoma and other advanced solid tumors. J. Clin. Oncol. 39:TPS4165–TPS
    [Google Scholar]
  46. 46.
    Bridgewater J, Meric-Bernstam F, Hollebecque A et al. 2020. Efficacy and safety of futibatinib in intrahepatic cholangiocarcinoma (iCCA) harboring FGFR2 fusions/other rearrangements: subgroup analyses of a phase II study (FOENIX-CCA2). Ann. Oncol. 31:S260–73
    [Google Scholar]
  47. 47.
    Simbolo M, Vicentini C, Ruzzenente A et al. 2018. Genetic alterations analysis in prognostic stratified groups identified TP53 and ARID1A as poor clinical performance markers in intrahepatic cholangiocarcinoma. Sci. Rep. 8:7119
    [Google Scholar]
  48. 48.
    Krook MA, Lenyo A, Wilberding M et al. 2020. Efficacy of FGFR inhibitors and combination therapies for acquired resistance in FGFR2-fusion cholangiocarcinoma. Mol. Cancer Ther. 19:847–57
    [Google Scholar]
  49. 49.
    Goyal L, Shi L, Liu LY et al. 2019. TAS-120 overcomes resistance to ATP-competitive FGFR inhibitors in patients with FGFR2 fusion-positive intrahepatic cholangiocarcinoma. Cancer Discov 9:1064–79
    [Google Scholar]
  50. 50.
    Goyal L, Saha SK, Liu LY et al. 2017. Polyclonal secondary FGFR2 mutations drive acquired resistance to FGFR inhibition in patients with FGFR2 fusion-positive cholangiocarcinoma. Cancer Discov. 7:252–63
    [Google Scholar]
  51. 51.
    Krook MA, Bonneville R, Chen HZ et al. 2019. Tumor heterogeneity and acquired drug resistance in FGFR2-fusion-positive cholangiocarcinoma through rapid research autopsy. Cold Spring Harb. Mol. Case Stud. 5:a004002
    [Google Scholar]
  52. 52.
    Kono M, Komatsuda H, Yamaki H et al. 2022. Immunomodulation via FGFR inhibition augments FGFR1 targeting T-cell based antitumor immunotherapy for head and neck squamous cell carcinoma. Oncoimmunology 11:2021619
    [Google Scholar]
  53. 53.
    Palakurthi S, Kuraguchi M, Zacharek SJ et al. 2019. The combined effect of FGFR inhibition and PD-1 blockade promotes tumor-intrinsic induction of antitumor immunity. Cancer Immunol. Res. 7:1457–71
    [Google Scholar]
  54. 54.
    Adachi Y, Kamiyama H, Ichikawa K et al. 2022. Inhibition of FGFR reactivates IFNγ signaling in tumor cells to enhance the combined antitumor activity of lenvatinib with anti-PD-1 antibodies. Cancer Res. 82:292–306
    [Google Scholar]
/content/journals/10.1146/annurev-med-042921-024707
Loading
/content/journals/10.1146/annurev-med-042921-024707
Loading

Data & Media loading...

  • Article Type: Review Article
This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error