New Relevant Evidence in Cholangiocarcinoma Biology and Characterization DOI Open Access

N. M. Porro,

Elena Spínola-Lasso, Mirella Pastore

и другие.

Cancers, Год журнала: 2024, Номер 16(24), С. 4239 - 4239

Опубликована: Дек. 19, 2024

Among solid tumors, cholangiocarcinoma (CCA) emerges as one of the most difficult to eradicate. The silent and asymptomatic nature this tumor, particularly in its early stages, well high heterogeneity at genomic, epigenetic, molecular levels delay diagnosis, significantly compromising efficacy current therapeutic options thus contributing a dismal prognosis. Extensive research has been conducted on pathobiology CCA, recent advances have made classification characterization new targets. Both targeted therapy immunotherapy emerged effective safe strategies for various types cancers, demonstrating potential benefits advanced CCA. Furthermore, deeper comprehension cellular components tumor microenvironment (TME) opened up possibilities innovative treatment methods. This review discusses evidence biology highlighting novel possible druggable

Язык: Английский

Understanding and Overcoming Resistance to Selective FGFR inhibitors Across FGFR2-Driven Malignancies DOI Creative Commons
Francesco Facchinetti, Yohann Loriot, Floriane Brayé

и другие.

Clinical Cancer Research, Год журнала: 2024, Номер 30(21), С. 4943 - 4956

Опубликована: Сен. 3, 2024

Abstract Purpose: Understanding resistance to selective FGFR inhibitors is crucial improve the clinical outcomes of patients with FGFR2-driven malignancies. Experimental Design: We analyzed sequential ctDNA, ± whole-exome sequencing, or targeted next-generation sequencing on tissue biopsies from tumors harboring activating FGFR2 alterations progressing pan-FGFR–selective inhibitors, collected in prospective UNLOCK program. FGFR2::BICC1 Ba/F3 and patient-derived xenograft models were used for functional studies. Results: Thirty-six included. In cholangiocarcinoma, at both reversible (e.g., pemigatinib erdafitinib) irreversible inhibitor futibatinib, polyclonal kinase domain mutations frequent (14/27 patients). Tumors other than cholangiocarcinoma shared same mutated residues, but polyclonality was rare (1/9 At 14 residues mutated—after only molecular brake N550 gatekeeper V565. Off-target PI3K/mTOR MAPK pathways found 11 patients, often together on-target mutations. progression a first inhibitor, 12 received futibatinib lirafugratinib (irreversible inhibitors), variable depending previous mechanisms. Two TSC1 PIK3CA benefited everolimus. cell viability assays pharmacologic studies xenografts, retained better activity against mutations, active recalcitrant V565L/F/Y. Conclusions: malignancies are characterized by high intra- interpatient heterogeneity, particularly cholangiocarcinoma. Resistance can be overcome sequential, molecularly oriented treatment strategies across tumors.

Язык: Английский

Процитировано

11

RAS signaling in carcinogenesis, cancer therapy and resistance mechanisms DOI Creative Commons

Xiaojuan Yang,

Hong Wu

Journal of Hematology & Oncology, Год журнала: 2024, Номер 17(1)

Опубликована: Ноя. 9, 2024

Variants in the RAS family (HRAS, NRAS and KRAS) are among most common mutations found cancer. About 19% patients with cancer harbor mutations, which typically associated poor clinical outcomes. Over past four decades, KRAS has long been considered an undruggable target due to absence of suitable small-molecule binding sites within its mutant isoforms. However, recent advancements drug design have made RAS-targeting therapies viable, particularly approval direct

Язык: Английский

Процитировано

7

A Phase I Study of KIN-3248, an Irreversible Small-molecule Pan-FGFR Inhibitor, in Patients with Advanced FGFR2/3-driven Solid Tumors DOI Creative Commons
Benjamin Garmezy, Mitesh J. Borad,

Rastilav Bahleda

и другие.

Cancer Research Communications, Год журнала: 2024, Номер 4(4), С. 1165 - 1173

Опубликована: Апрель 11, 2024

Abstract Purpose: Despite efficacy of approved FGFR inhibitors, emergence polyclonal secondary mutations in the kinase domain leads to acquired resistance. KIN-3248 is a selective, irreversible, orally bioavailable, small-molecule inhibitor FGFR1-4 that blocks both primary oncogenic and resistance alterations. Experimental Design: A first-in-human, phase I study was conducted patients with advanced solid tumors harboring FGFR2 and/or FGFR3 gene alterations (NCT05242822). The objective determination MTD/recommended II dose (RP2D). Secondary exploratory objectives included antitumor activity, pharmacokinetics, pharmacodynamics, molecular response by circulating tumor DNA (ctDNA) clearance. Results: Fifty-four received doses ranging from 5 50 mg daily across six cohorts. Intrahepatic cholangiocarcinoma (48.1%), gastric (9.3%), urothelial (7.4%) were most common tumors. Tumors harbored (68.5%) or (31.5%) alterations—23 (42.6%) prior inhibitors. One dose-limiting toxicity (hypersensitivity) occurred cohort 1 (5 mg). Treatment-related, adverse events hyperphosphatemia, diarrhea, stomatitis. MTD/RP2D not established. Exposure proportional concordant hyperphosphatemia. Five partial responses observed; 4 naïve pretreated patients. Pretreatment ctDNA profiling confirmed FGFR2/3 63.3% cases clearance at cycle 2 associated radiographic response. Conclusion: trial terminated early for commercial considerations; therefore, RP2D Preliminary clinical data suggest safe, oral favorable pharmacokinetic parameters, though further escalation required nominate MTD/RP2D. Significance: rationally designed, next generation selective inhibitor, effective interfering wild-type mutant signaling. Clinical indicate safe signal activity. Translational science support mechanism action serum phosphate exposure, paired biopsies suggested phospho-ERK inhibition (a downstream target FGFR2/3), may act as RECIST surrogate.

Язык: Английский

Процитировано

5

Genomic correlates of response and resistance to the irreversible FGFR1-4 inhibitor futibatinib based on biopsy and circulating tumor DNA profiling DOI Creative Commons
Lipika Goyal,

Daniel DiToro,

Antoine Hollebecque

и другие.

Annals of Oncology, Год журнала: 2024, Номер unknown

Опубликована: Дек. 1, 2024

Язык: Английский

Процитировано

5

A Model for Decoding Resistance in Precision Oncology: Acquired Resistance to FGFR inhibitors in Cholangiocarcinoma DOI Creative Commons

Love Goyal,

Daniel DiToro,

Francesco Facchinetti

и другие.

Annals of Oncology, Год журнала: 2024, Номер unknown

Опубликована: Дек. 1, 2024

Язык: Английский

Процитировано

5

Cholangiocarcinoma Targeted Therapies: Mechanisms of Action and Resistance DOI
Haley Ellis, Chiara Braconi, Juan W. Valle

и другие.

American Journal Of Pathology, Год журнала: 2024, Номер unknown

Опубликована: Дек. 1, 2024

Язык: Английский

Процитировано

3

Case Report: FGFR2 inhibitor resistance via PIK3CA and CDKN2A/B in an intrahepatic cholangiocarcinoma patient with FGFR2-SH3GLB1 fusion DOI Creative Commons

Nadja Ballin,

A. Ott,

Olga Seibel-Kelemen

и другие.

Frontiers in Oncology, Год журнала: 2025, Номер 15

Опубликована: Апрель 7, 2025

FGFR2 fusions occur in up to 14% of patients with intrahepatic cholangiocarcinoma (iCCA) and have been considered as therapeutic target for FGFR inhibitors (FGFRi). However, response targeted treatment may be limited due the emergence various resistance mechanisms. We report a case recurrent iCCA 43-year-old patient fusion, who was treated Lenvatinib. Next-generation sequencing (NGS) tumor-normal DNA tumor RNA under Lenvatinib confirmed however no further molecular mutation observed. After failure FGFRi (Lenvatinib Infigratinib) ten months later, repeated NGS analysis revealed new gain-of-function PIK3CA homozygous deletion CDKN2A/B, potentially representing an acquired mechanism. The emerging inhibitor has implications subsequent strategies.

Язык: Английский

Процитировано

0

Oncogenic Signalling Pathways in Cancer Immunotherapy: Leader or Follower in This Delicate Dance? DOI Open Access
Douglas Cartwright, Andrew Kidd, Sonam Ansel

и другие.

International Journal of Molecular Sciences, Год журнала: 2025, Номер 26(9), С. 4393 - 4393

Опубликована: Май 6, 2025

Immune checkpoint inhibitors have become a mainstay of treatment in many solid organ malignancies. Alongside this has been the rapid development identification and targeting oncogenic drivers. The presence alterations drivers not only predicts response to target therapy but can modulate immune microenvironment influence immunotherapy. Combining with targeted agents is an attractive therapeutic option overlapping toxicity profiles may limit clinical use some combinations. In addition, there growing evidence shared resistance mechanisms that alter immunotherapy when it used after therapy. Understanding complex interaction between drivers, vital for selecting right treatment, at time patient. review, we summarise preclinical four common on inhibitor response, combination therapies, mechanisms. We highlight need more randomised trials investigating both sequential

Язык: Английский

Процитировано

0

Precision Oncology in Hepatopancreatobiliary Cancer Surgery DOI
Timothy E. Newhook, Susan Tsai, Funda Meric‐Bernstam

и другие.

Surgical Oncology Clinics of North America, Год журнала: 2024, Номер 33(2), С. 343 - 367

Опубликована: Янв. 24, 2024

Язык: Английский

Процитировано

2

Targeted therapies in biliary tract cancer—when precision becomes imprecise DOI Creative Commons
Colm J. O’Rourke,

Jakob Vasehus Schou,

Jesper B. Andersen

и другие.

ESMO Gastrointestinal Oncology, Год журнала: 2024, Номер 5, С. 100085 - 100085

Опубликована: Авг. 13, 2024

Язык: Английский

Процитировано

1