Format

Send to

Choose Destination
Blood. 2019 Apr 22. pii: blood.2018881029. doi: 10.1182/blood.2018881029. [Epub ahead of print]

IGF1R as druggable target mediating PI3K-δ inhibitor resistance in a murine model of chronic lymphocytic leukemia.

Author information

1
Internal Medicine III, University of Ulm, Germany.
2
University of Ulm, Germany.
3
Department of Internal Medicine III, Ulm University, Germany.
4
Internal Medicine III, University Hospital Ulm, Germany.
5
Division of Experimental Oncology, Università Vita-Salute San Raffaele C.F 97187560152, Italy.
6
Gilead Sciences Inc., United States.
7
Hematology, Oncology and Tumorimmunology, Charite University Medicine, Virchow Campus, Germany.
8
Ulm University.
9
Hematology, Oncology and Tumorimmunology, Charité University Medicine, Germany.
10
Gilead Sciences Inc.
11
Department of Internal Medicine III, University Hospital Medical Center, Germany.
12
The Feinstein Institute for Medical Research, United States.
13
North Shore-Long Island Jewish Health System.
14
Department of Haematology, University of Heidelberg, Germany.
15
Molecular Genetics, German Cancer Research Center, Germany.
16
Gilead Sciences, Inc., United States.
17
Department of Internal Medicine III, University of Ulm, Germany.
18
University Hospital Ulm, Germany.
19
Department of Internal Medicine III, University of Ulm, Germany stephan.stilgenbauer@uniklinik-ulm.de.

Abstract

Targeted therapy is currently revolutionizing the treatment of cancers, but resistance evolves against these therapies and derogates their success. The PI3K-δ inhibitor idelalisib has been approved for CLL and NHL treatment, but the mechanisms conferring resistance in a subset of patients are unknown. Here, we modelled resistance to PI3K-δ inhibitor in vivo using a serial tumor transfer and treatment scheme in mice. Whole exome sequencing identified no recurrent mutation explaining resistance to PI3K-δ inhibitor. In the murine model resistance to PI3K-δ inhibitor occurred due to a signalling switch mediated by consistent and functionally relevant activation of Insulin-like growth factor 1 receptor (IGF1R), resulting in enhanced MAPK signalling in the resistant tumors. Overexpression of IGF1R in vitro demonstrated its prominent role in PI3K-δ inhibitor resistance. IGF1R upregulation in PI3K-δ inhibitor resistant tumors was mediated by functional activation and enhanced nuclear localization of forkhead box protein O1 (FOXO1) transcription factors and glycogen synthase kinase 3 beta (GSK3B). In human CLL, high IGF1R expression was associated with trisomy-12. CLL cells from an idelalisib treated patient showed decreased sensitivity to idelalisib in vitro concomitant with enhanced MAPK signalling and strong upregulation of IGF1R upon idelalisib exposure. Our results thus highlight that alternative signalling cascades are playing a predominant role in the resistance and survival of cancer cells under PI3K-δ inhibition. We also demonstrate that these pathway alterations can serve as therapeutic targets, as inhibition of IGF1R offered efficacious salvage treatment for PI3K-δ inhibitor resistant tumors in vitro and in vivo.

PMID:
31010847
DOI:
10.1182/blood.2018881029

Supplemental Content

Full text links

Icon for HighWire
Loading ...
Support Center