Akt Activation Mediates Acquired Resistance to Fibroblast Growth Factor Receptor Inhibitor BGJ398

Datta, Jharna; Damodaran, Srinivasan; Parks, Hannah; Ocrainiciuc, Cristina; Miya, Jharna; Yu, Lianbo; Gardner, Elijah P.; Samorodnitsky, Eric; Wing, Michele R.; Bhatt, Darshna; Hays, John L.; Reeser, Julie W.; Roychowdhury, Sameek

doi:10.1158/1535-7163.mct-15-1010

Cited by 84 publications

(69 citation statements)

References 49 publications

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“…Concurrent with these studies, there has been much focus on pre-empting acquired clinical resistance to FGFR inhibitors (30,41,42). In a recent study, the acquisition of a gatekeeper mutation, p.V564F, in FGFR2 was found to confer resistance in three cholangiocarcinoma patients with acquired clinical resistance to BGJ398 (43).…”

Section: Discussionmentioning

confidence: 99%

Acquired Resistance to FGFR Inhibitor in Diffuse-Type Gastric Cancer through an AKT-Independent PKC-Mediated Phosphorylation of GSK3β

Lau

Teng

Huang

et al. 2018

Molecular Cancer Therapeutics

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Preclinical models of diffuse-type gastric cancer (DGC) that reliably predict clinical activity of novel compounds are lacking. To overcome the problem of poor tumor cellularity in DGC, we used cells from malignant ascites to establish DGC patientderived xenograft (PDX) models that recapitulate the primary cancer. Cells in PDX model GAGA6 with FGFR2 amplification were sensitive to AZD4547, a potent FGFR inhibitor that is being clinically evaluated for FGFR-aberrant cancer types. Intermittent in vivo treatment of GAGA6 tumors with AZD4547 gave rise to PDX tumors with acquired resistance to AZD4547, GAGA6-R. Surprisingly, there were no mutations in the FGFR2 gene in GAGA6-R, negating gatekeeper mutations as a mechanism of drug resistance. Phosphorylation of FGFR2 and downstream signaling molecules AKT/PKB and MAPK/ERK remained inhibited by AZD4547. Further analysis of signaling pathways identified AKT-independent phosphorylation and inhibition of GSK3b as a mechanism of drug resistance in GAGA6-R cells. Treatment of GAGA6-R cells with protein kinase C (PKC) inhibitor H7 in combination with AZD4547 led to dephosphorylation and activation of GSK3b with concomitant downregulation of MCL-1 and BCL-XL. Combined treatment with AZD4547 and H7 in vitro synergistically enhanced cell death in GAGA6-R but not GAGA6 cells. Furthermore, midostaurin, a multikinase inhibitor with PKC-inhibiting activity, in part reversed resistance of GAGA6-R tumor to AZD4547 in vivo. Our results suggest that upon challenge with FGFR inhibitors, FGFR2-amplified tumors that are highly dependent on FGFR2 signaling for survival rapidly develop resistance by switching to a PKC-mediated inhibition of GSK3b to gain a survival advantage.

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Section: Discussionmentioning

confidence: 99%

Acquired Resistance to FGFR Inhibitor in Diffuse-Type Gastric Cancer through an AKT-Independent PKC-Mediated Phosphorylation of GSK3β

Lau

Teng

Huang

et al. 2018

Molecular Cancer Therapeutics

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“…In patients with FGFR2 fusion-positive ICC in a phase II trial, FGFR inhibitor NVP-BGJ398 displayed promising efficacy, but when several patients became resistant to NVP-BGJ398, a genomic analysis of cell-free circulating tumor DNA revealed that the patients had acquired a mutation in the FGFR2 kinase domain that conferred resistance to FGFR inhibition. Moreover, several preclinical studies suggested multiple resistant mechanisms, such as MET/ERBB receptor kinase activation (17)(18)(19), PI3K pathway activation (20,21), PKC-mediated inhibition of GSK3b (22), epithelialmesenchymal transition (23), acquired FGFR2 rearrangement (24), and so on. Therefore, acquired resistance to FGFR inhibition is a growing issue, and understanding its mechanism would provide a novel therapeutic option for overcoming it.…”

Section: Introductionmentioning

confidence: 99%

Acquired JHDM1D–BRAF Fusion Confers Resistance to FGFR Inhibition in FGFR2-Amplified Gastric Cancer

Sase¹,

Nakanishi²,

Aida³

et al. 2018

Molecular Cancer Therapeutics

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gene is frequently amplified in gastric cancer. Recently, targeting FGFR2 has drawn attention as a form of gastric cancer therapy, and FGFR-selective inhibitors have shown promising efficacy in clinical studies. Because overcoming acquired resistance is a common problem with molecular targeting drugs, we investigated a resistant mechanism of FGFR inhibitors using the gastric cancer cell line SNU-16, which harbors amplification. We established single-cell clones of FGFR inhibitor-resistant SNU-16 (AZD-R) by continuous exposure to AZD4547, a selective FGFR inhibitor. To screen the genetic alterations acquired in AZD-R, we ran a comparative genomic hybridization assay and found an amplification of Chr7q34 region. The chromosomal breakpoints were located between the 12th and the 13th exon of jumonji C domain containing histone demethylase 1 homolog D () and between the 3rd and the 4th exon of We sequenced cDNA of the AZD-R clones and found fusion kinase, which has previously been identified in primary ovarian cancer. Because JHDM1D-BRAF fusion lacks a RAS-binding domain, the dimerization of JHDM1D-BRAF was enhanced. A cell growth inhibition assay using MEK inhibitors and RAF-dimer inhibitors indicated the dependence of AZD-R clones for growth on the MAPK pathway. Our data provide a clinical rationale for using a MEK or RAF dimer inhibitor to treat -amplified gastric cancer patients who have acquired resistance through the JHDN1D-BRAF fusion..

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“…While on-target resistance mutations in the FGFR2 kinase domain (N649H/K, V564F, E656A, L617V, K641R and K659M) have been detected in circulating tumour DNA in the context of FGFR2 translocations in cholangiocarcinoma patients who have received infigratinib (33,34), such mutations have yet to be identified in cancers with FGFR3 molecular alterations. Preclinical studies have shown that upregulation of the AKT pathway as well as ligand-mediated activation of ErbB2/3 are bypass signalling pathways in the context of acquired resistance to infigratinib in the RT112M cell line (35,36). In the paradigm of intrinsic resistance, Herrera-Abreu et al, has shown that EGFR activation is an escape mechanism to PD173074 treatment and that a combination of gefitinib and PD173074 could overcome drug resistance in urothelial cancer lines harbouring FGFR3 molecular alterations (23).…”

Section: Discussionmentioning

confidence: 99%

Targeting the Src pathway enhances the efficacy of selective FGFR inhibitors in cancers with FGFR3 alterations

Lima

Atkinson

Bunney

et al. 2020

Preprint

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Selective FGFR inhibitors such as infigratinib (BGJ398) and erdafitinib (JNJ-42756493) have been evaluated in clinical trials for cancers with FGFR3 molecular alterations, particularly in urothelial carcinoma patients. However, a substantial proportion of these patients (up to 50%) display intrinsic resistance to these drugs and receive minimal clinical benefit. There is thus an unmet need for alternative therapeutic strategies to overcome primary resistance to selective FGFR inhibitors. In this study, we demonstrate that cells expressing cancerassociated activating FGFR3 mutants and the FGFR3-TACC3 fusion showed primary resistance to infigratinib in long-term colony formation assays in both NIH-3T3 and urothelial carcinoma models. We find that expression of these FGFR3 molecular alterations resulted in elevated constitutive Src activation compared to wildtype FGFR3 and that cells co-opted this pathway as a means to achieve intrinsic resistance to infigratinib. Targeting the Src pathway with low doses of the kinase inhibitor dasatinib synergistically sensitized multiple urothelial carcinoma lines harbouring endogenous FGFR3 alterations to infigratinib. Our preclinical data provides evidence that supports the use of dasatinib in combination with selective FGFR inhibitors as a means to overcome intrinsic drug resistance in the salvage therapy setting in cancer patients with FGFR3 molecular alterations.

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Akt Activation Mediates Acquired Resistance to Fibroblast Growth Factor Receptor Inhibitor BGJ398

Cited by 84 publications

References 49 publications

Acquired Resistance to FGFR Inhibitor in Diffuse-Type Gastric Cancer through an AKT-Independent PKC-Mediated Phosphorylation of GSK3β

Acquired Resistance to FGFR Inhibitor in Diffuse-Type Gastric Cancer through an AKT-Independent PKC-Mediated Phosphorylation of GSK3β

Acquired JHDM1D–BRAF Fusion Confers Resistance to FGFR Inhibition in FGFR2-Amplified Gastric Cancer

Targeting the Src pathway enhances the efficacy of selective FGFR inhibitors in cancers with FGFR3 alterations

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