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Targeting the Fibroblast Growth Factor Receptor (FGFR) Family in Lung Cancer

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Targeting the Fibroblast Growth Factor Receptor (FGFR) Family in Lung Cancer cells Review Targeting the Fibroblast Growth Factor Receptor (FGFR) Family in Lung Cancer Laura Pacini , Andrew D. Jenks, Nadia Carvalho Lima and Paul H. Huang * Division of Molecular Pathology, The Institute of Cancer Research, London SM2 5NG, UK; [email protected] (L.P.); [email protected] (A.D.J.); nadia.sofi[email protected] (N.C.L.) * Correspondence: [email protected] Abstract: Lung cancer is the most common cause of cancer-related deaths globally. Genetic alterations, such as amplifications, mutations and translocations in the fibroblast growth factor receptor (FGFR) family have been found in non-small cell lung cancer (NSCLC) where they have a role in cancer initiation and progression. FGFR aberrations have also been identified as key compensatory bypass mechanisms of resistance to targeted therapy against mutant epidermal growth factor receptor (EGFR) and mutant Kirsten rat sarcoma 2 viral oncogene homolog (KRAS) in lung cancer. Targeting FGFR is, therefore, of clinical relevance for this cancer type, and several selective and nonselective FGFR inhibitors have been developed in recent years. Despite promising preclinical data, clinical trials have largely shown low efficacy of these agents in lung cancer patients with FGFR alterations. Preclinical studies have highlighted the emergence of multiple intrinsic and acquired resistance mechanisms to FGFR tyrosine kinase inhibitors, which include on-target FGFR gatekeeper mutations and activation of bypass signalling pathways and alternative receptor tyrosine kinases. Here, we review the landscape of FGFR aberrations in lung cancer and the array of targeted therapies under clinical evaluation. We also discuss the current understanding of the mechanisms of resistance to Citation: Pacini, L.; Jenks, A.D.; FGFR-targeting compounds and therapeutic strategies to circumvent resistance. Finally, we highlight Lima, N.C.; Huang, P.H. Targeting the our perspectives on the development of new biomarkers for stratification and prediction of FGFR Fibroblast Growth Factor Receptor inhibitor response to enable personalisation of treatment in patients with lung cancer. (FGFR) Family in Lung Cancer. Cells 2021, 10, 1154. https://doi.org/ Keywords: FGFR; lung cancer; tyrosine kinase inhibitors; drug resistance 10.3390/cells10051154 Academic Editors: Antoni Wiedlocha and Malgorzata Zakrzewska 1. Introduction Received: 2 April 2021 The Fibroblast Growth Factor Receptor (FGFR) family plays a central role in a broad Accepted: 7 May 2021 range of important physiological events during embryonic development and adult re- Published: 10 May 2021 sponse to injury, tissue repair and regeneration [1–3]. FGFRs are key to the regulation of a number of cellular processes such as survival, proliferation, migration, differentiation and Publisher’s Note: MDPI stays neutral metabolism [4–7]. They are also involved in the development and progression of several with regard to jurisdictional claims in cancer types, including lung cancer. Here we review the landscape of FGFR aberrations published maps and institutional affil- inherent in lung cancer or found in patients that progress on targeted therapy treatment iations. as a compensatory bypass pathway. We also discuss the preclinical and clinical advances in targeting these aberrations, as well as the acquired resistance mechanisms to FGFR inhibitors and therapeutic approaches to overcome drug resistance. Copyright: © 2021 by the authors. 1.1. An Overview of the FGFR Family Licensee MDPI, Basel, Switzerland. The FGFR family is composed of four highly conserved receptor tyrosine kinases This article is an open access article (RTKs), FGFR1-4, as well as a fifth member known as FGFR-like protein (FGFR5). FGFR1-4 distributed under the terms and are transmembrane proteins activated by the binding of a variety of fibroblast growth factor conditions of the Creative Commons (FGF) ligands. While FGFR1-4 are active kinases, FGFR5 which also localises to the cell Attribution (CC BY) license (https:// membrane and binds FGF ligands, lacks the kinase domain and does not possess kinase creativecommons.org/licenses/by/ activity [8]. There are 22 FGF ligands in mammals that range in size from 150–300 amino 4.0/). Cells 2021, 10, 1154. https://doi.org/10.3390/cells10051154 https://www.mdpi.com/journal/cells Cells 2021,, 1010,, 1154 1154 2 of 22 2 of 22 areacids, 22 FGF and ligands crystallography in mammals studiesthat range have in size shown from that 150-300 there amino is a homologous acids, and crystallog- core domain raphyin all studies FGFs have composed shown ofthat around there is 125 a homolo aminogous acids. coreThe domain region in outsideall FGFs the composed conserved of core aroundis comprised 125 amino of acids. variable The region amino outside acid sequences the conserved that core determine is comprised the of selectivity variable amino of binding acidof distinctsequences FGFs that todetermine different th FGFRe selectivity family of members binding of [9 distinct]. FGFs FGFs bind to to different FGFR, resultingFGFR in familyreceptor members dimerisation [9]. FGFswhich bind to drives FGFR, theresult transphosphorylationing in receptor dimerisation of the which intracellular drives the tyrosine transphosphorylationkinase domain inducing of the theintracellular recruitment tyrosine of adaptor kinase proteinsdomain inducing responsible the forrecruitment the activation of of adaptorseveral proteins downstream responsible signalling for the pathways activation through of several which downstream these receptors signalling exert pathways their biological throughfunctions which (Figure these1 recept) [ 10ors]. Examplesexert their biological of the most functions common (Figure signalling 1) [10]. Examples pathways of activatedthe mostby FGFRscommon are signalling the rat sarcoma pathways kinase activated (RAS) by FGFRs and mitogen-activated are the rat sarcoma protein kinase kinase(RAS) and (MAPK), mitogen-activatedthe phosphatidylinositol protein kinase 3-kinase/protein (MAPK), the phosphatidylinositol kinase B (PI3K/AKT), 3-kinase/protein signal transduction kinase B and (PI3K/AKT), signal transduction and activation of transcription (STAT), the c-Jun N-terminal activation of transcription (STAT), the c-Jun N-terminal kinase (JNK) and SRC pathways [4–7]. kinase (JNK) and SRC pathways [4–7]. Figure 1. Simplified overview of FGFR canonical signalling pathways. FGFs bind to FGFR inducing Figurereceptor 1. Simplified dimerisation overview which of thenFGFR drives canonical the transphosphorylationsignalling pathways. FGFs of the bind tyrosine to FGFR kinase inducing domain in receptor dimerisation which then drives the transphosphorylation of the tyrosine kinase domain in the intracellular compartment of the cell. The intracellular portion of active FGFR is phosphorylated the intracellular compartment of the cell. The intracellular portion of active FGFR is phosphorylated atat multiple multiple tyrosine tyrosine sites. sites. In the In theC-terminus, C-terminus, tyrosine tyrosine phosphorylation phosphorylation acts as acts a docking as a docking site for site for moleculesmolecules containing containing SH2 SH2 domains domains such as such PLC asγ. PLCPhosphorylationγ. Phosphorylation of PLCγ hydrolyses of PLCγ hydrolyses PIP2 to pro- PIP2 to duceproduce DAG DAGand IP3, and inducing IP3, inducing the release the releaseof calciu ofm calcium cations cationsand subsequent and subsequent activation activation of PKC. In of PKC. theIn intracellular the intracellular juxtamembrane juxtamembrane region of region FGFR, of ph FGFR,osphorylation phosphorylation leads to the leads recruitment to the recruitment of FRS2 of whichFRS2 then which acts then as a secondary acts as a secondary docking protein docking to form protein two toindependent form two independentcomplexes. One complexes. complex One is FRS2-GRB2-SOS that activates RAS, which in turn activates the MAPK pathway. A second com- complex is FRS2-GRB2-SOS that activates RAS, which in turn activates the MAPK pathway. A second plex is FRS2-GRB2-GAB1, which drives the activation of PI3K/AKT pathway. Other pathways are alsocomplex known is to FRS2-GRB2-GAB1, be activated by FGFR which such drives as STAT, the activation p38 MAPK, of PI3K/AKTJNK, SRC and pathway. RSK2 pathways. Other pathways Collectively,are also known these topathways be activated play multiple by FGFR roles such in as cell STAT, survival, p38 MAPK,growth, JNK,migration, SRC anddifferentiation RSK2 pathways. andCollectively, metabolism. these FGFR pathways signalling play is regulated multiple rolesby receptor in cell survival,internalisation growth, upon migration, ubiquitination differentiation by CBLand or metabolism. by negative FGFRmodulation signalling by different is regulated proteins by (shown receptor in internalisation bold red) such uponas MKP, ubiquitination SEF and by SPRY.CBL The or by yellow negative stars modulationrepresent tyrosine by different phosphor proteinsylation sites. (shown HS: in heparin bold red)sulphate; such FRS2: as MKP, FGFR SEF and substrate 2; PLCγ: protein phospholipase Cγ; PIP2: phosphatidylinositol 4,5-bisphosphate; DAG: SPRY. The yellow stars represent tyrosine phosphorylation sites. HS: heparin sulphate; FRS2: FGFR diacylglycerol; IP3: IP3 inositol 1,4,5-triphosphate; Ca2+: calcium; PKC: protein kinase C; GRB2: γ γ growthsubstrate factor 2; PLCreceptor-bond: protein 2; phospholipase SOS: son of se Cvenless;; PIP2: MAPK: phosphatidylinositol mitogen-activated 4,5-bisphosphate; protein kinase; DAG: 2+
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