Kinome RNAi Screens Reveal Synergistic Targeting of MTOR and FGFR1 Pathways for Treatment of Lung Cancer and HNSCC

Abstract

The fibroblast growth factor receptor FGFR1 is a therapeutic target under investigation in multiple solid tumors and clinical trials of selective tyrosine kinase inhibitors (TKI) are underway. Treatment with single TKI represents a logical step towards 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 multi-kinase FGFR-active inhibitor. We identified and validated a synthetic lethal interaction between Mammalian Target of Rapamycin (MTOR) and ponatinib in non-small cell lung carcinoma cells. Additionally, treatment with MTOR-targeting shRNAs and pharmacological 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. Further, they suggest clinical efficacy of treatments for FGFR1-driven lung cancers and HNSCC may be achieved by combining MTOR inhibitors and FGFR-specific TKIs.

Cisplatin Increases Sensitivity to FGFR Inhibition in Patient-Derived Xenograft Models of Lung Squamous Cell Carcinoma

“…It is unknown if the distinct mechanisms of FGFR1 activation or if other aberrantly activated kinases are causing the differing downstream effects of FGFR inhibition in PDXs 788 and 926 and further experiments would be necessary to investigate such conclusions. Using two FGFRi-sensitive lung cancer cell lines, Singleton and colleagues suggested that combination therapy with mTOR inhibitor AZD2014 and FGFR inhibitor AZD4547 improved response compared to single agents (47). However, we observed response to FGFR inhibitor and PI3K/mTOR inhibitor combination only in PDX 926, a tumor with strong AKT activity that was not reduced by treatment with BGJ398 alone.…”

In�vitro antitumor effects of FGFR and PI3K inhibitors on human papillomavirus positive and negative tonsillar and base of tongue cancer cell lines

“…To our knowledge this is the first time, that drugs against FGFR and PI3K were used in combination for treatment of HPV + and HPV -TSCC/BOTSCC cell lines, although the combination of AZD4547 and an MTOR inhibitor has been used on a nasopharyngeal carcinoma cell line (44). Furthermore, to our knowledge, these drugs have not been used under physiological conditions as single treatments on patients with HPV + TSCC/BOTSCC or combined treatments for patients with HPV + or HPV -TSCC/BOTSCC.…”

Melanoma Therapeutic Strategies that Select against Resistance by Exploiting MYC-Driven Evolutionary Convergence

“…To measure the ability of cell lines to form colonies from a single cell, clonogenic growth assays were performed as previously described (Singleton et al, 2015). Briefly, 100 cells were seeded per well in 12-well plates.…”