Reference Detail

Ref Type Journal Article
PMID (26359452)
Authors Singleton KR, Hinz TK, Kleczko EK, Marek LA, Kwak J, Harp T, Kim J, Tan AC, Heasley LE
Title Kinome RNAi Screens Reveal Synergistic Targeting of MTOR and FGFR1 Pathways for Treatment of Lung Cancer and HNSCC.
Journal Cancer research
Vol 75
Issue 20
Date 2015 Oct 15
URL
Abstract Text The FGFR1 is a therapeutic target under investigation in multiple solid tumors and clinical trials of selective tyrosine kinase inhibitors (TKI) are underway. Treatment with a single TKI represents a logical step toward personalized cancer therapy, but intrinsic and acquired resistance mechanisms limit their long-term benefit. In this study, we deployed RNAi-based functional genomic screens to identify protein kinases controlling the intrinsic sensitivity of FGFR1-dependent lung cancer and head and neck squamous cell cancer (HNSCC) cells to ponatinib, a multikinase FGFR-active inhibitor. We identified and validated a synthetic lethal interaction between MTOR and ponatinib in non-small cell lung carcinoma cells. In addition, treatment with MTOR-targeting shRNAs and pharmacologic inhibitors revealed that MTOR is an essential protein kinase in other FGFR1-expressing cancer cells. The combination of FGFR inhibitors and MTOR or AKT inhibitors resulted in synergistic growth suppression in vitro. Notably, tumor xenografts generated from FGFR1-dependent lung cancer cells exhibited only modest sensitivity to monotherapy with the FGFR-specific TKI, AZD4547, but when combined with the MTOR inhibitor, AZD2014, significantly attenuated tumor growth and prolonged survival. Our findings support the existence of a signaling network wherein FGFR1-driven ERK and activated MTOR/AKT represent distinct arms required to induce full transformation. Furthermore, they suggest that clinical efficacy of treatments for FGFR1-driven lung cancers and HNSCC may be achieved by combining MTOR inhibitors and FGFR-specific TKIs.

Filtering

  • Case insensitive filtering will display rows where any text in any cell matches the filter term
  • Simple literal full or partial string matches
  • Separate multiple filter terms with a spaces, order doesn't matter (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 a longer phrase which contains spaces "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
Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
FGFR1 positive lung large cell carcinoma sensitive AZD4547 + Sirolimus Preclinical - Cell culture Actionable In a preclinical study, AZD4547 and Rapamune (sirolimus) synergistically inhibited survival of FGFR1-dependent lung large cell carcinoma cells in culture (PMID: 26359452). 26359452
FGFR1 positive lung large cell carcinoma sensitive AZD4547 + Vistusertib Preclinical - Cell line xenograft Actionable In a preclinical study, AZD4547 and Vistusertib (AZD2014) synergistically inhibited survival of FGFR1-dependent lung large cell carcinoma cells in culture and in cell line xenograft models (PMID: 26359452). 26359452
FGFR1 positive lung large cell carcinoma sensitive AZD4547 + AZD8055 Preclinical - Cell culture Actionable In a preclinical study, AZD4547 and AZD8055 synergistically inhibited survival of FGFR1-dependent lung large cell carcinoma cells in culture (PMID: 26359452). 26359452
FGFR1 positive lung adenocarcinoma sensitive AZD4547 + AZD8055 Preclinical - Cell culture Actionable In a preclinical study, AZD4547 and AZD8055 synergistically inhibited survival of FGFR1-dependent lung adenocarcinoma cells in culture (PMID: 26359452). 26359452
FGFR1 positive lung adenocarcinoma sensitive AZD4547 + Vistusertib Preclinical - Cell line xenograft Actionable In a preclinical study, AZD4547 and Vistusertib (AZD2014) synergistically inhibited survival of FGFR1-dependent lung adenocarcinoma cells in culture and in cell line xenograft models (PMID: 26359452). 26359452
FGFR1 positive lung adenocarcinoma sensitive AZD4547 + Sirolimus Preclinical - Cell culture Actionable In a preclinical study, AZD4547 and Rapamune (sirolimus) synergistically inhibited survival of FGFR1-dependent lung adenocarcinoma cells in culture (PMID: 26359452). 26359452
FGFR1 positive head and neck squamous cell carcinoma sensitive AZD4547 + Vistusertib Preclinical - Cell culture Actionable In a preclinical study, AZD4547 and Vistusertib (AZD2014) synergistically inhibited survival of FGFR1-dependent head and neck squamous cell carcinoma cells in culture (PMID: 26359452). 26359452