Zentralbl Chir 2019; 144(S 01): S84
DOI: 10.1055/s-0039-1694178
Vorträge – DACH-Jahrestagung: nummerisch aufsteigend sortiert
Georg Thieme Verlag KG Stuttgart · New York

Combined mTOR inhibition and chemotherapy as an effective strategy to treat KRAS-mutant lung cancer

RW Peng
1   Division of General Thoracic Surgery, Inselspital, Bern University Hospital, University of Bern, Switzerland
2   Department for BioMedical Research (DBMR), Inselspital, Bern University Hospital, University of Bern, Switzerland
,
SQ Liang
1   Division of General Thoracic Surgery, Inselspital, Bern University Hospital, University of Bern, Switzerland
2   Department for BioMedical Research (DBMR), Inselspital, Bern University Hospital, University of Bern, Switzerland
,
ED Bührer
3   Department of Medical Oncology, Inselspital, Bern University Hospital, University of Bern, Switzerland
4   Department for BioMedical Research (DBMR), Inselspital, Bern University Hospital, University of Bern, Switzerland
,
S Berezowska
5   Institute of Pathology, University of Bern, Switzerland
,
TM Marti
1   Division of General Thoracic Surgery, Inselspital, Bern University Hospital, University of Bern, Switzerland
2   Department for BioMedical Research (DBMR), Inselspital, Bern University Hospital, University of Bern, Switzerland
,
D Xu
1   Division of General Thoracic Surgery, Inselspital, Bern University Hospital, University of Bern, Switzerland
2   Department for BioMedical Research (DBMR), Inselspital, Bern University Hospital, University of Bern, Switzerland
,
L Froment
1   Division of General Thoracic Surgery, Inselspital, Bern University Hospital, University of Bern, Switzerland
2   Department for BioMedical Research (DBMR), Inselspital, Bern University Hospital, University of Bern, Switzerland
,
H Yang
1   Division of General Thoracic Surgery, Inselspital, Bern University Hospital, University of Bern, Switzerland
2   Department for BioMedical Research (DBMR), Inselspital, Bern University Hospital, University of Bern, Switzerland
,
SRR Hall
1   Division of General Thoracic Surgery, Inselspital, Bern University Hospital, University of Bern, Switzerland
2   Department for BioMedical Research (DBMR), Inselspital, Bern University Hospital, University of Bern, Switzerland
,
E Vassella
5   Institute of Pathology, University of Bern, Switzerland
,
Z Yang
1   Division of General Thoracic Surgery, Inselspital, Bern University Hospital, University of Bern, Switzerland
2   Department for BioMedical Research (DBMR), Inselspital, Bern University Hospital, University of Bern, Switzerland
,
GJ Kocher
1   Division of General Thoracic Surgery, Inselspital, Bern University Hospital, University of Bern, Switzerland
2   Department for BioMedical Research (DBMR), Inselspital, Bern University Hospital, University of Bern, Switzerland
,
MA Amrein
3   Department of Medical Oncology, Inselspital, Bern University Hospital, University of Bern, Switzerland
4   Department for BioMedical Research (DBMR), Inselspital, Bern University Hospital, University of Bern, Switzerland
,
C Riether
3   Department of Medical Oncology, Inselspital, Bern University Hospital, University of Bern, Switzerland
4   Department for BioMedical Research (DBMR), Inselspital, Bern University Hospital, University of Bern, Switzerland
,
AF Ochsenbein
3   Department of Medical Oncology, Inselspital, Bern University Hospital, University of Bern, Switzerland
4   Department for BioMedical Research (DBMR), Inselspital, Bern University Hospital, University of Bern, Switzerland
,
RA Schmid
1   Division of General Thoracic Surgery, Inselspital, Bern University Hospital, University of Bern, Switzerland
2   Department for BioMedical Research (DBMR), Inselspital, Bern University Hospital, University of Bern, Switzerland
› Author Affiliations
Further Information

Publication History

Publication Date:
04 September 2019 (online)

Also available at
 

Background:

KRAS-mutant cancers represent the most common type of human malignancies defined by genetic alterations and, ironically, the largest subset of tumors that cannot be effectively targeted by currently available therapeutics, such as chemotherapy, owing to intrinsic and acquired resistance.

Material and method:

In vitro models that recapitulate acquired resistance to chemotherapy in KRAS-mutant lung cancer were generated and subjected to drug screening. Acquired vulnerabilities in chemo-resistant KRAS-mutant lung cancer cells were identified and characterized by in vitro, ex vivo approaches and in preclinical mouse models.

Result:

Examination of clinical specimens from patients treated with chemotherapy revealed that KRAS-mutant, but not KRAS-wild-type, lung adenocarcinoma exhibits hyperactivation in mammalian target of rapamycin (mTOR). Further analysis showed that chemo-resistant KRAS-mutant lung cancer cells exquisitely depend on mTOR signaling for survival and are therefore selectively vulnerable to mTOR inhibition. Importantly, we demonstrated that mTOR inhibitors and chemotherapy synergize in suppressing KRAS-mutant cancer cells in vitro and in vivo.

Conclusion:

Our study identifies mTOR as a key determinant of the sensitivity to chemotherapy. As mTOR inhibitors are clinically approved drugs, our results validate a readily translatable combination strategy to treat KRAS-mutant lung cancer.