1 INTRODUCTION

Bladder cancer (BLCA) accounts for the 10th most common cancer globally, with more than 550,000 newly diagnosed cases and over 220,000 annual deaths worldwide [1, 2]. Male gender increases the risk for BLCA (4:1), making it the 6^th most common cancer among all cancer types worldwide [1, 2]. According to the American Cancer Society prediction, one out of every twenty-eight men will develop BLCA during their lifetime (source: https://www.cancer.org/). Nevertheless, the biological females are diagnosed at more advanced and deadlier stages of BLCA [2].

Around 95% of BLCAs are urothelial cancer, originating from urothelial cells within one of the cellular layers of bladder epithelium [2]. Based on the tumor's local invasion, BLCA is classified into non-muscle-invasive disease (NMIBC) and muscle-invasive disease (MIBC), accounting for ∼80% and ∼20% of BLCAs, respectively [1, 3]. With the emergence of knowledge about genetic alterations in BLCA, the association of these alterations with different subtypes has been unveiled [1].

The five-year survival rate for NMIBC stands at approximately 70%-96% [3, 4]. However, depending on the MIBC disease stage, it drops from 38% to a meager 6% in metastatic BLCA [5].

The diagnosis and management of BLCA places substantial economic pressure on healthcare systems as, particularly MIBC, is the costliest cancer type per patient, with estimated costs in the US reaching approximately $6 billion annually [6].

2 FGFR3 ALTERATIONS AND THEIR ROLE IN BLCA AND BEYOND

Fibroblast Growth Factor Receptor (FGFR) alterations, and in particular, FGFR3 mutations, are one of the most frequent alterations in BLCA, associated with ∼60% of the NMIBCs and at least 15% of the MIBCs [1, 2]. Figure 1 illustrates two BLCA categories, emphasizing their correlation with distinct stages and diverse subtypes, all within FGFR3 status.

In 1999 Cappellen et al. [7] described recurrent activating FGFR3 in BlCA and cervical cancer. In 2006, Bernard-Pierrot et al. [8] showed that mutated FGFR3b (S249C), the predominant isoform in epithelial cells, has oncogenic properties as demonstrated by its ability to transform NIH-3T3 cells, and when transformed cells implanted in immunocompromised mice formed tumors. Bernard-Pierrot et al. [8] showed that FGFR3 knockdown and FGFR chemical inhibition in BLCA MGH-U3 cells, harboring the same mutated isoform, suppressed cell proliferation and anchorage-independent growth. Later, Tomlinson et al. [9] reported similar findings in another BLCA cell line (97-7) with the same mutation. Apart from mutation or overexpression, FGFR3 can also be activated in BLCA through chromosomal rearrangements that generate constitutively activated fusion genes [10]. Specifically, FGFR3-transforming acid coiled-coil 3 (TACC3) fusions resulting from 4p16.3 rearrangements and a t(4;7) translocation generating an FGFR3-BAI1-associated protein 2-like 1 (BAIAP2L1) fusion were identified in several BLCA cell lines and tissue samples [10]. These fusion proteins have lost their Phospholipase C gamma 1 (PLCγ1) binding site. They can transform NIH-3T3 cells. They can induce activation of the ERK pathway, but not the PLCγ1, in immortalized normal human urothelial cells, suggesting their potential as targets for FGFR-targeted therapy in BLCA [10].

In 2014, during a Cancer Genome Atlas project study, a comprehensive genetic analysis of 131 urothelial carcinomas discovered FGFR3 alterations as one of the genetic hallmarks of urothelial bladder carcinoma [11]. More recently, FGFR3 mutations have been suggested as one of the potential therapeutic targets in advanced BLCA [12]. The consensus classification of BLCA had concluded that the high frequency of FGFR3 mutations, translocations, and FGFR3 activation signature in advanced BLCA could suggest that these tumors may be collectively responsive to FGFR-targeted therapeutics [12]. The authors reiterated the results of studies that showed a considerable group of MIBC patients who either harbored FGFR3 mutations or were identified with high FGFR3 expression signatures could benefit from FGFR3-targeted therapies [12]. Of note, later, the benefit of FGFR3 inhibition has been limited to patients with FGFR3 mutations and not those with solely high FGFR3 expression [13, 14].

Komura et al. integrated the three subtyping systems, Consensus [12], Baylor [15], and UROMOL [16], in BLCA categories (NMIBC vs. MIBC) in which the subtyping was not originally described [17]. The variations in subtype frequencies could be associated with either NMIBC or MIBC. For example, the class I, differentiated (vs. basal), and LumP subtypes were more prevalent in NMIBC than in MIBC [17]. However, most subtyping systems could not distinguish between NMIBC and MIBC in an absolute manner [17]. The UROMOL class 3 subtype, with the highest frequency of FGFR3 alterations, was mostly confined to NMIBC [17].

Kinase domain mutations were predominantly enriched among basal/squamous subtypes [17]. Gene Set Enrichment Analysis (GSEA) also revealed that basal/squamous and epithelial signatures characterized MIBC. Moreover, Komura et al. [17] showed that FGFR3 alterations in MIBC, in addition to luminal subtypes, can involve epithelial subtypes, including both the basal and squamous types.

Of note, the association of FGFR3 alterations with the induction of basal markers in this category warrants further investigations of whether resistance mechanisms and pathways activated by FGFR3 and, consequently, co-targets to tackle these resistance mechanisms differ between NMIBC and MIBC.

A significant proportion, up to 50% of BLCA patients, including a subset of those with advanced disease, carry FGFR3 mutations [2]. These are primarily point mutations, followed by less frequent structural variants (∼14:1 ratio) involving fusion with other genes, such as TACC3 [3, 18]. To investigate this further, we consulted cBioPortal to query 4,732 samples from 3,993 patients across 19 non-redundant studies (date of data retrieval: September 10^th, 2023). Our analysis revealed three prominent mutational hotspots within the FGFR3 coding sequence (the reference is the FGFR3c sequence), namely S249, R248, and Y373 (Figure 2). Interestingly, these hotspots do not involve the tyrosine kinase domain but induce a conformational change that leads to constitutive protein activity and triggers its downstream signaling output [7, 19, 20]. Further, following the approach described previously [21], we manually curated the dataset, cross-referenced patient and sample IDs, and retained only the earliest samples. Our curation corroborated that the three most frequently occurring FGFR3 mutations in BLCA were S249C (APOBEC-type motif [22]), Y373C, and R248C, accounting for 49%, 13%, and 12% of the samples, respectively. These findings are, in principle, consistent with previous reports [23].

A multi-omic analysis of 124 NMIBC and 265 MIBC patient samples and 35 adjacent normal tissue samples by Komura et al. [17] has provided insights into the differential FGFR3 mutational status among the Asian and Western populations.

In the Asian population, FGFR3 SNPs, including Q29H, G65R, L164V, T450M, and A720S, appeared enriched at the germline level, though these mutations were not enriched in BLCA patients, and no established associations with clinical outcomes among BLCA patients were identified [17].

Unlike the Western population, FGFR3 mutations within the kinase domain, specifically K650E and T757P, were more prevalent yet showed no conclusive changes in clinical outcomes [17]. Notably, these mutations were more recurrent in MIBCs [17]. Additionally, Komura et al. [17] discovered two novel FGFR3 fusions involving NSD2 and SPON2.

Regarding the frequency of FGFR3 alterations among subtypes, 54% and 94% of class I and class III UROMOL subtypes, respectively, and 42% of the MIBC LumP (consensus) subtype harbored these alterations [17].

Mutant FGFR3 is shown to have transforming capacity in a context-dependent and variant-specific manner [24]. As unraveled by di Martino et al. [24], variants could exhibit distinctive downstream signaling output and differential impacts on proliferation. For instance, in a human urothelial cellular model, FGFR^S249C but not FGFR^K652E could activate the PLCγ1 and induce cellular proliferation (see Figure 3 for a simplified illustration of FGFR3 signaling). Conversely, in a mouse embryonic fibroblast cell line, all three FGFR3 variants could activate the PLCγ1 and exhibited cell transforming capacity [24].

Indeed, FGFR3 is frequently mutated or overexpressed in BLCA. Assessing mutation status and receptor expression levels may help define the patient population that could benefit from FGFR-targeted therapies [25].

Of note, Shi et al. [26] have recently shown that human FGFR3^S249C alone can initiate luminal-like papillary tumors in a transgenic mouse model with higher incidence among male mice. Interestingly, the formed tumors exhibited a similar expression profile as class I and class III human BLCA [26]. Both subtypes belonged to NMIBC and are known to be enriched with FGFR3 mutations [26]. The authors reported that FGFR3^S249C-induced tumor initiation correlates with FGFR3 tissue expression levels [26]. As the authors reiterated, in previous studies, other FGFR3 variants, such as K644E, the murine equivalent of human K652E, had failed to induce tumors without other cooperating factors [26, 27].

Today, when patients relapse on immune checkpoint inhibitors, they may be eligible for FGFR3-targeted therapy [2]. Therapeutics targeting FGFR3 encompass a range of approaches in terms of medicinal chemistry, including multi-kinase inhibitors, selective kinase inhibitors, and monoclonal antibodies directed against FGFR3 [28-30]. The first two categories have made more significant progress in the clinical trial phases [30]. Selective FGFR inhibitors like erdafitinib and rogaratinib are advanced in clinical trials [3, 28, 29]. In particular, erdafitinib, which has shown selectivity towards FGFRs and high potency, has been granted FDA approval for metastatic urothelial carcinoma with FGFR3 and FGFR2 alterations and is currently being explored in other BLCA settings [3, 14, 28, 29, 31–36]. In one study leading to accelerated FDA approval, erdafitinib's median duration of response in patients with advanced BLCA was shown to be 5.6 months (95% CI, 4.2 to 7.2) [14].

Recently, erdafitinib has been clinically explored among different groups of FGFR mutated BLCA patients [14, 31-35, 37]. For instance, among high-risk NMIBC patients who harbored FGFR3 or FGFR2 genetic alterations and were refractory to BCG therapy, oral erdafitinib was shown to have more favorable outcomes in terms of recurrence-free survival (RFS) compared to intravesical chemotherapy (median RFS: ∼16.9 months vs. ∼11.6 months) [38]. Moreover, a novel drug delivery system for site-specific and sustained intravesical delivery of erdafitinib is also being developed [39].

Clinically available compounds targeting FGFRs are pan-FGFR inhibitors with varying degrees of activity against each FGFR isoform. However, this broad FGFR targeting comes at the cost of adverse events. For instance, the FGFR1 activity of these compounds is suggested to be associated with hyperphosphatemia, while anti-FGFR4 targeting is linked to diarrhea [40].

Nail damage, alopecia, dry mouth, stomatitis, blurred vision, central serous retinopathy, and hand-foot syndrome are recurrent adverse events observed among patients receiving FGFR inhibitors [30]. While these adverse events are often below grade 3 toxicities, they may necessitate temporary dose withdrawal or dose reduction until the adverse event is resolved [14, 30-34, 36-39, 40–46].

Hyperphosphatemia is rather a shared adverse event caused by different FGFR inhibitors. At least 60% of patients treated with FGFR inhibitors experience some extent of hyperphosphatemia.

FGF23-FGFR1-klotho axis controls phosphate levels. When FGF23 binds to FGFR1, it inhibits 25-hydroxyvitamin D 1α-hydroxylase, leading to the breakdown of 1,25-dihydroxyvitamin D (1,25(OH)2D), and blocks sodium-phosphate co-transporters in the proximal renal tubules, reducing phosphate reabsorption [30, 40, 47]. FGFR inhibitors block this pathway, preventing the breakdown of 1,25(OH)2D and the inhibition of sodium-phosphate co-transporters, which increases both 1,25(OH)2D levels and phosphate reabsorption in the kidneys. By disrupting the FGF23-FGFR1-klotho axis that typically limits phosphate reabsorption, FGFR inhibitors cause hyperphosphatemia through increased intestinal phosphate absorption due to higher 1,25(OH)2D levels and increased renal phosphate reabsorption and decreased excretion [30, 40, 47].

Maintaining a low-phosphate diet and prescribing phosphate binders can prevent and manage hyperphosphatemia, reducing therapy discontinuation risk [30]. While interventions like phosphate binders and dietary phosphate restriction are necessary to manage the common hyperphosphatemia caused by FGFR inhibitors, these measures can paradoxically lead to hypophosphatemia in some patients. Unlike hyperphosphatemia, which typically is low-grade, hypophosphatemia resulting from overcorrection may manifest as a higher-grade (grade ≥3) adverse event [48].

Interestingly, serum phosphate levels have emerged as a robust pharmacodynamic marker for the FGFR inhibitor erdafitinib [14, 49]. Increases in serum phosphate levels, a consequence of FGFR inhibition by erdafitinib, were found to strongly correlate with positive clinical responses and improved outcomes in treated patients [14, 49, 50]. As such, based on pharmacodynamic and pharmacokinetic modeling, a target serum phosphate threshold of 5.5 mg/dL (1.8 mmol/L) has been defined, indicative of an effective erdafitinib dose capable of achieving the desired pharmacologic effect [14, 49, 50]. A study proposes initiating erdafitinib at a dose of 8 mg, followed by an escalation to 9 mg between Days 14 and 21. While minimizing dose-limiting interventions, this approach maximized the proportion of patients achieving the target serum phosphate concentrations of 5.5-7 mg/dL [50].

In theory, selective FGFR3 inhibitors should effectively inhibit FGFR3 while enhancing the therapeutic safety profile. Efforts in this regard have been made, and several FGFR3-targeting monoclonal antibodies with enhanced selectivity for FGFR3 have been preclinically and clinically explored [51-55]. FGFR inhibitor toxicity is not exclusively due to their pan-FGFR effects but can be associated with their targeting potential towards other proteins, such as VEGFR2 [56]. Efforts are being made to develop inhibitors with enhanced selectivity towards FGFR3 over VEGFR2 [56].

In the following lines, we revisit FGFR3, a less-understood receptor tyrosine kinase, beyond its role in BLCA.

FGFR3 is one of the four conventional members of the FGFR family [57]. In 1986, Drohan's lab isolated the coding sequence of FGF1, one of the cognate ligands of FGFRs, from the human brain cDNA library [58]. Today, we acknowledge at least eighteen human FGF ligands (twenty-two unique FGFs in rodents and humans) that bind to different FGFR isoforms, triggering diverse signal transduction processes and resulting in distinct cellular outcomes [29, 57, 59]. Four FGFR receptors are encoded from four different chromosomes, and FGFR3 is encoded from chromosome 4 [29, 60]. FGFR3 can be activated by FGF1, FGF2, FGF4, FGF5, FGF6, FGF8, FGF9, FGF16, FGF17, FGF18, FGF19, FGF20, FGF21, or FGF23 in human or mouse [3, 57]. FGFR3, like the other three members of the related Receptor Tyrosine Kinase family (RTK), has functions beyond its role in cancer, from early embryogenesis to cell homeostasis throughout mammalian cell life [57]. FGFR3 possesses three extracellular domains where ligand binding occurs, a juxta-membranous domain and an intracellular domain where the tyrosine kinase domain is positioned [29, 57]. Upon ligand binding, FGFR3 undergoes activation and dimerization [57, 61, 62]. Notably, despite conjecture, the mechanisms and extent of FGFR3's involvement in heterodimerization events remain poorly understood. Following ligand binding and the initiation of dimerization, FGFRs may experience transphosphorylation of their tyrosine kinase domains, and subsequently, via their C-terminal tails, they facilitate the binding and activation of adaptor proteins, setting in motion downstream signaling cascades [3, 57] (Figure 3). Notably, nonliganded FGFR3 has basal dimerization capacity that can be augmented in some mutant forms of FGFR3 [61, 62].

FGFRs, including FGFR3, can be genetically altered in solid and liquid tumors [63-68], and therefore, endeavors have been dedicated to therapeutically targeting such alterations [69-72]. Apart from BLCA, where FGFR3 mutations are prevalent, other human cancers can be identified with these mutations, albeit at a much lower frequency. These cancer types, among others, include uterine and cervical cancers [73, 74], glioblastoma [75], multiple myeloma [76], penile cancer [77], non-melanoma skin cancer [78], melanoma [79], small bowel cancer [80] and non-small cell lung cancer [81, 82].

FGFR3 has attracted attention not only in the context of cancer. Interestingly, activating FGFR3 mutations, particularly S249C, can be recurrently found in benign skin conditions such as seborrheic keratoses [83, 84].

FGFR3 has been extensively examined in bone repair,-remodeling, and skeletal disorders [85-93]. Herein, unlike in aforementioned cancers, FGFR3's role is rather suppressive. In particular, FGFR3 can restrict the proliferation of chondrocytes, and its signaling can lie behind skeletal disorders such as achondroplasia and thanatophoric dysplasia [94]. Interestingly, activating FGFR3 germline mutations have been linked to skeletal disorders in humans and animal models [29, 87-89, 95–97]. FGFR3 negatively influences chondrocyte balance, viability, and differentiation by sabotaging the related autophagy machinery in achondroplasia [85]. FGFR3 can suppress sheep growth plate chondrocyte proliferation by limiting telomerase activity during bone elongation in a Thyroid hormone-dependent (T3) manner [86]. Interestingly, in addition to several FGF ligands, FGFR3 is the target of T3 [86].

In mice where chondrocyte FGFR3 was knocked out, there was a notable increase in osteoblast count and bone formation [98]. This effect was further elucidated through chondrocyte-osteoblast co-culture experiments, which demonstrated that the absence of FGFR3 in chondrocytes stimulated the differentiation and mineralization of osteoblasts, accompanied by the up-regulation of genes including Ihh, Bmp2, Bmp4, Bmp7, Wnt4, and Tgf-β1, along with a down-regulation of Nog expression [98]. Conversely, FGF18, a high-affinity ligand for FGFR3, has shown protective effects in osteoarthritis [93, 99]. Of note, a variant of FGFR3 has been reported in Camptodactyly, Tall Stature, and Hearing Loss (CATSHL) Syndrome, which counteract the wild-type FGFR3 function in a dominant-negative manner [100-102].

Due to the complexity of FGFs and FGFRs signaling, the full picture of FGFR3's role in bone and cartilage pathogenesis remains to be elucidated.

This duality of the FGFR3 role has also been reported in cancer. For instance, in colorectal cancer (CRC), the FGFR3 role seems Janus-faced [103]. Due to aberrant alternative splicing and activation of cryptic splice sequences, FGFR3 was reported to be frequently inactivated in CRC [103]. Conversely, FGFR3 overexpression in CRC has been associated with a more invasive phenotype [104]. A recent study on Hepatocellular carcinoma (HCC) deciphers truncated FGFR3's role in cancer, or at least in HCC [105]. FGFR3∆7-9, lacking the IgG III domain involved in FGF binding, exhibits increased affinity for FGF compared to wild-type FGFR3 [105]. FGFR3∆7-9 promotes HCC cell proliferation, migration, and metastasis both in vitro and in vivo [105]. Interestingly, FGFR3∆7-9 directly interacts with TET2, a tumor suppressor, phosphorylating it at Y1902, thereby promoting TET2 ubiquitination and degradation and unleashing the AKT pathway and its oncogenic subsequences, which is no longer suppressed by the TET2-PTEN axis [105].

In one study in pancreatic cancer, FGFR3 has been shown to have a tumor-suppressing role in cells with epithelial features while exhibiting oncogenic properties in cells with mesenchymal characteristics [106].

FGFRs present a high degree of homology to other known RTKs like vascular endothelial growth factor receptor (VEGFR) and platelet-derived growth factor receptor (PDGFR) [107]. In terms of signaling output, a great extent of similarities can be observed with other RTKs, such as the renowned Epidermal Growth Factor Receptor (EGFR). Those common features are not limited to the mechanism of action, but these receptors also share downstream effectors and, as such, shared cellular events [3, 57, 108-110]. FGFR3 activation yields at least four distinct pathway activities, including the RAS-RAF-MEK-MAPK, PI3K/AKT, Calcium signaling, and Signal Transducer and Activator of Transcription (STAT) pathways (Figure 3) [24, 29, 92, 106, 111–113]. These pathways are known to be significantly influenced by receptor tyrosine kinases (RTKs) like EGFR as well [92, 113–117]. As such, it comes as no surprise that regulators of FGFR3 signaling are also shared between FGFR3 and EGFR. Indeed, CBL, SPRY, Dusp-6, and SEF are among the known regulators of FGFR3 signaling that have been previously studied in the context of EGFR signal transduction and regulation [3, 118–122].

In BLCA with aberrant FGFR3 activation due to translocation and point mutation, the role of the FGFR3/MYC feedback loop has been unveiled [123]. FGFR3 upregulates MYC expression by increasing MYC mRNA levels via p38α MAPK activation. Additionally, FGFR3 stabilizes the MYC protein by AKT-mediated phosphorylation of GSK3β, preventing MYC degradation by the proteasome. As such, a positive feedback loop was discovered where activated FGFR3 upregulates MYC levels, which in turn upregulates FGFR3 expression, and disrupting this FGFR3/MYC loop decreased bladder cancer cell viability in vitro and tumor growth in vivo [123].

Still, we do not fully grasp the extent of FGFR3 signaling and its unique impact. As FGFR3 shares similarities with other receptors like EGFR, these commonalities might help us uncover more about FGFR3's function and vulnerabilities.

3 MUTATED FGFR3: SENSITIVITY AND RESISTANCE TO TARGETED THERAPIES IN BLCA

Unsurprisingly, the resistance mechanism to FGFR3 inhibition in BLCA resembles those observed in EGFR-targeted therapeutics. Indeed, just as resistance to some EGFR inhibitors can arise due to the emergence of resistant clones with secondary mutations at the gatekeeper T790 site of EGFR, secondary mutations in gatekeeper FGFR3 residue have also been reported in response to FGFR inhibition.

Resistant mechanisms are not limited to on-target secondary mutations but can also involve bypassing mechanisms [124-126]. In the case of FGFR3-mutated BLCA under FGFR inhibition therapy, cells may find ways to bypass signaling through EGFR in an AKT-dependent manner [127].

Moreover, FGFR3 has a pivotal role in shaping the TME landscape and, as such, response to therapies that impact TME.

In the following paragraphs, we delve into some recent preclinical and clinical highlights of discoveries of mechanisms that contribute to mutated FGFR3 BLCA resistance to approved targeted therapies.

4 DISCUSSION AND CONCLUSIONS

As the revisit of recent findings in this writing suggests, FGFR3 mutations in BLCA may not serve as conclusive predictive markers for lack of response to CPIs. Considering the EMT status of the TME and the tumor subtype, more sophisticated algorithms are needed to establish effective consensus for FGFR3-mutated BLCA response to CPIs.

Moreover, a combination of FGFR1/3 inhibition and CPIs holds promise for further clinical exploration in BLCA.

The state of the art regarding the predictive and prognostic value of mutational profile of FGFR3 altered tumors is still in its infancy. An important lesson from the study by Guercio et al. [23] is that an updated NGS is essential before starting the FGFR3 inhibition therapy.

Whether innate or acquired, resistance to FGFR3 inhibitors in BLCA is not an isolated phenomenon limited to FGFR3 inhibitors targeting BLCA or even cancer therapy. We have drawn valuable lessons from the HIV field, where combined treatments, referred to as “drug cocktails,” have led to more favorable and durable clinical outcomes [158]. In the realm of cancer targeting, mainly since the New Era of Personalized Medicine in 1999 [159], the focus has primarily been on exploring monotherapies, with a recurrent pursuit of more effective combined treatments. One prominent example of such an approach is the combined inhibition of RAF and MEK in targeting BRAF^V600E mutant melanoma [160]. It is worth noting that upfront combinatorial treatments, if tolerable, not only may enhance and deepen the initial response but also have the potential to significantly delay the emergence of acquired resistance over the long term. For instance, the combination of EGFR and VEGF targeting demonstrated a delay in developing secondary T790M EGFR mutations and enhanced the response in EGFR L858R/T790M-positive cancer cells [161]. Since then, more evidence has supported the argument of upfront combinatorial treatments in EGFR mutant cancer [162] and beyond [163]. Piro Lito introduced the fitness threshold model, which suggests that cancer cells exposed to combinatorial treatments with a higher threshold, as opposed to monotherapy, may be at a greater risk of experiencing unfavorable outcomes [164].

In 2009, Nobel Prize laureate William G. Kaelin Jr. adopted Theodosius Dobzhansky's concept of synthetic lethality as a conceptual framework for cancer target discovery [165]. This approach has effectively widened targeting options in all areas of cancer. As such, exploring synthetically lethal (co)targets with FGFR3 holds promise in BLCA. As the revisit of precedent studies into unraveling different resistance mechanisms in FGFR3-mutated BLCA treated with different FGFR inhibitors revealed, targeting the differentially expressed genes has not often proven effective in producing a meaningful response. It is worth noting that genetic screens, such as CRISPR screens, can be highly beneficial in tackling the significant heterogeneity observed in resistance mechanisms against FGFR inhibition by directly discovering valid co-targets.

An intriguing aspect of both preclinical and clinical studies aiming to unravel the resistance mechanism to FGFR3 inhibition is the absence of findings at the genotype or transcriptome level in a subset of samples. Hence, the question could be investigated by delving into less-explored facets of FGFR3's direct or indirect influence, such as its interactions with non-coding RNAs.

In summary, mutant FGFR3 has demonstrated its significance as an oncogenic element and a promising target in BLCA. On the other hand, short-lasting clinical benefits and the rise of resistance in all patients upon FGFR3 inhibition monotherapy underscore the need for the discovery of FGFR3 co-targets and the uncovering of its unexplored functions and vulnerabilities in BLCA.

AUTHOR CONTRIBUTIONS

MN and MP conceived and conceptualized the concept of this writing and authored the manuscript with all other co-authors’ scientific and authoring contributions. KK generated most of the figures with contributions and supervision from MN and MP. All authors critically revised the manuscript.

CONFLICT OF INTEREST STATEMENT

The authors declare no conflict of interest.

FUNDING

Not applicable.

ETHICAL APPROVAL AND CONSENT TO PARTICIPATE

Not applicable.