Reference Detail

Contact

Missing content? – Request curation!

Request curation for specific Genes, Variants, or PubMed publications.

Have questions, comments, or suggestions? - Let us know!

Email us at : ckbsupport@genomenon.com

Ref Type Journal Article
PMID (39706336)
Authors Goyal L, DiToro D, Facchinetti F, Martin EE, Peng P, Baiev I, Iyer R, Maurer J, Reyes S, Zhang K, Majeed U, Berchuck JE, Chen CT, Walmsley C, Pinto C, Vasseur D, Gordan JD, Mody K, Borad M, Karasic T, Damjanov N, Danysh BP, Wehrenberg-Klee E, Kambadakone AR, Saha SK, Hoffman ID, Nelson KJ, Iyer S, Qiang X, Sun C, Wang H, Li L, Javle M, Lin B, Harris W, Zhu AX, Cleary JM, Flaherty KT, Harris T, Shroff RT, Leshchiner I, Parida L, Kelley RK, Fan J, Stone JR, Uboha NV, Hirai H, Sootome H, Wu F, Bensen DC, Hollebecque A, Friboulet L, Lennerz JK, Getz G, Juric D
Title A Model for Decoding Resistance in Precision Oncology: Acquired Resistance to FGFR inhibitors in Cholangiocarcinoma.
Journal Vol Issue Date Pages Journal Short Title
Annals of oncology : official journal of the European Society for Medical Oncology 2024 Dec 18 Ann Oncol
URL
Abstract Text Fibroblast growth factor receptor (FGFR) inhibitors have significantly improved outcomes for patients with FGFR-altered cholangiocarcinoma, leading to their regulatory approval in multiple countries. However, as with many targeted therapies, acquired resistance limits their efficacy. A comprehensive, multimodal approach is crucial to characterizing resistance patterns to FGFR inhibitors.This study integrated data from six investigative strategies: cell-free DNA, tissue biopsy, rapid autopsy, statistical genomics, in vitro and in vivo studies, and pharmacology. We characterized the diversity, clonality, frequency, and mechanisms of acquired resistance to FGFR inhibitors in patients with FGFR-altered cholangiocarcinoma. Clinical samples were analyzed longitudinally as part of routine care across 10 institutions.Among 138 patients evaluated, 77 met eligibility, yielding a total of 486 clinical samples. Patients with clinical benefit exhibited a significantly higher rate of FGFR2 kinase domain mutations compared to those without clinical benefit (65% vs 10%, p<0.0001). We identified 26 distinct FGFR2 kinase domain mutations, with 63% of patients harboring multiple. While IC50 assessments indicated strong potency of pan-FGFR inhibitors against common resistance mutations, pharmacokinetic studies revealed that low clinically achievable drug concentrations may underly polyclonal resistance. Molecular brake and gatekeeper mutations predominated, with 94% of patients with FGFR2 mutations exhibiting one or both, whereas mutations at the cysteine residue targeted by covalent inhibitors were rare. Statistical genomics and functional studies demonstrated that mutation frequencies were driven by their combined effects on drug binding and kinase activity rather than intrinsic mutational processes.Our multimodal analysis led to a model characterizing the biology of acquired resistance, informing the rational design of next-generation FGFR inhibitors. FGFR inhibitors should be small, high-affinity, and selective for specific FGFR family members. Tinengotinib, a novel small molecule inhibitor with these characteristics, exhibited preclinical and clinical activity against key resistance mutations. This integrated approach offers a blueprint for advancing drug resistance research across cancer types.

Filtering

  • Case insensitive filtering will display rows if any text in any cell matches the filter term
  • Use simple literal full or partial string matches
  • Separate multiple filter terms with a space. Any order may be used (i. e. a b c and c b a are equivalent )
  • Filtering will only apply to rows that are already loaded on the page. Filtering has no impact on query parameters.
  • Use quotes to match on a longer phrase with spaces (i.e. "mtor c1483f")

Sorting

  • Generally, the default sort order for tables is set to be first column ascending; however, specific tables may set a different default sort order.
  • Click on any column header arrows to sort by that column
  • Hold down the Shift key and click multiple columns to sort by more than one column. Be sure to set ascending or descending order for a given column before moving on to the next column.

Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
FGFR2 L262_A266delinsD indel unknown FGFR2 L262_A266delinsD results in a deletion of five amino acids from aa 262 to aa 266 within Ig-like C2-type domain 3 of the Fgfr2 protein, combined with the insertion of an aspartic acid (D) at the same site (UniProt.org). L262_A266delinsD has been identified in the scientific literature (PMID: 39706336), but has not been biochemically characterized and therefore, its effect on Fgfr2 protein function is unknown (PubMed, Jan 2025).
FGFR2 Q621L missense unknown FGFR2 Q621L (corresponds to Q620L in the canonical isoform) lies within the protein kinase domain of the Fgfr2 protein (UniProt.org). Q621L has been identified in sequencing studies (PMID: 39706336), but has not been biochemically characterized and therefore, its effect on Fgfr2 protein function is unknown (PubMed, Jan 2025).
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
FGFR2 C382R FGFR2 M538I FGFR2 N550D FGFR2 V565I intrahepatic cholangiocarcinoma predicted - sensitive Tinengotinib Case Reports/Case Series Actionable In a clinical case study, Tinengotinib (TT-00420) treatment resulted in 37% tumor shrinkage in a patient with intrahepatic cholangiocarcinoma harboring FGFR2 C382R, N550D, V565I, and M538I (PMID: 39706336). 39706336
FGFR2 rearrange NRAS Q61K cholangiocarcinoma predicted - resistant Pemigatinib Case Reports/Case Series Actionable In a retrospective analysis, a cholangiocarcinoma patient harboring an FGFR2 rearrangement progressed on treatment with Pemazyre (pemigatinib) and was found to have acquired NRAS Q61K via cell-free DNA (PMID: 39706336). 39706336
FGFR2 C383R FGFR2 N550D FGFR2 N550K FGFR2 V565L cholangiocarcinoma predicted - resistant Erdafitinib Case Reports/Case Series Actionable In a retrospective analysis, a cholangiocarcinoma patient harboring FGFR2 C383R progressed on treatment with Balversa (erdafitinib) and was found to have acquired FGFR2 N550K and V565L via cell-free DNA, and FGFR2 N550D via cell-free DNA and tissue biopsy (PMID: 39706336; NCT01703481). 39706336
FGFR2 C383R cholangiocarcinoma predicted - sensitive Erdafitinib Case Reports/Case Series Actionable In a retrospective analysis, Balversa (erdafitinib) treatment resulted in a partial response with a progression-free survival of 9.3 months in a cholangiocarcinoma patient harboring FGFR2 C383R (PMID: 39706336; NCT01703481). 39706336
FGFR2 rearrange FGFR2 N550D FGFR2 N550H FGFR2 N550K FGFR2 N550T FGFR2 V565I FGFR2 V565L cholangiocarcinoma predicted - resistant Pemigatinib Case Reports/Case Series Actionable In a retrospective analysis, a cholangiocarcinoma patient harboring an FGFR2 rearrangement progressed on treatment with Pemazyre (pemigatinib) and was found to have acquired FGFR2 N550K, N550D, N550T, N550H, and V565I via cell-free DNA, and FGFR2 V565L via cell-free DNA and tissue biopsy (PMID: 39706336). 39706336
FGFR2 L262_A266delinsD NRAS Q61K cholangiocarcinoma predicted - resistant Futibatinib Case Reports/Case Series Actionable In a retrospective analysis, a cholangiocarcinoma patient harboring FGFR2 L262_A266delinsD progressed on treatment with Lytgobi (futibatinib) and was found to have acquired NRAS Q61K via cell-free DNA (PMID: 39706336; NCT02052778). 39706336