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	Vol	Issue	Date	Pages	Journal Short Title
Cancer research	75	20	2015 Oct 15	4398-406	Cancer Res

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.

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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

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
FGFR1 positive	lung large cell carcinoma	sensitive	Fexagratinib + 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	head and neck squamous cell carcinoma	sensitive	Fexagratinib + 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
FGFR1 positive	lung adenocarcinoma	sensitive	AZD8055 + Fexagratinib	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 large cell carcinoma	sensitive	AZD8055 + Fexagratinib	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	Fexagratinib + 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	lung adenocarcinoma	sensitive	Fexagratinib + 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 large cell carcinoma	sensitive	Fexagratinib + 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