Evasion of programmed cell death represents a critical form of oncogene addiction in cancer cells. Understanding the molecular mechanisms underpinning cancer cell survival despite the oncogenic stress could provide a molecular basis for potential therapeutic interventions. Here we explore the role of pro-survival genes in cancer cell integrity during clonal evolution in non-small cell lung cancer (NSCLC). We identify gains of MCL-1 at high frequency in multiple independent NSCLC cohorts, occurring both clonally and subclonally. Clonal loss of functional TP53 is significantly associated with subclonal gains of MCL-1. In mice, tumour progression is delayed upon pharmacologic or genetic inhibition of MCL-1. These findings reveal that MCL-1 gains occur with high frequency in lung adenocarcinoma and can be targeted therapeutically.
- Munkhbaatar, E.
- Dietzen, M.
- Agrawal, D.
- Anton, M.
- Jesinghaus, M.
- Boxberg, M.
- Pfarr, N.
- Bidola, P.
- Uhrig, S.
- Höckendorf, U.
- Meinhardt, A. L.
- Wahida, A.
- Heid, I.
- Braren, R.
- Mishra, R.
- Warth, A.
- Muley, T.
- Poh, P. S. P.
- Wang, X.
- Fröhling, S.
- Steiger, K.
- Slotta-Huspenina, J.
- van Griensven, M.
- Pfeiffer, F.
- Lange, S.
- Rad, R.
- Spella, M.
- Stathopoulos, G. T.
- Ruland, J.
- Bassermann, F.
- Weichert, W.
- Strasser, A.
- Branca, C.
- Heikenwalder, M.
- Swanton, C.
- McGranahan, N.
- Jost, P. J.
Keywords
- Animals
- Antineoplastic Agents/*pharmacology/therapeutic use
- Apoptosis/drug effects/genetics
- Carcinoma, Non-Small-Cell Lung/diagnostic imaging/drug therapy/*genetics/pathology
- Cell Line, Tumor
- Cell Survival/drug effects/genetics
- Clonal Evolution
- DNA Copy Number Variations
- Datasets as Topic
- Disease Models, Animal
- Disease Progression
- Humans
- Lung/diagnostic imaging/pathology
- Lung Neoplasms/diagnostic imaging/drug therapy/*genetics/pathology
- Mice
- Mice, Transgenic
- Mutation
- Myeloid Cell Leukemia Sequence 1 Protein/antagonists & inhibitors/*genetics
- Primary Cell Culture
- Prospective Studies
- Proto-Oncogene Proteins p21(ras)/genetics
- Pyrimidines/pharmacology/therapeutic use
- RNA-Seq
- Retrospective Studies
- Spheroids, Cellular
- Thiophenes/pharmacology/therapeutic use
- Tumor Burden/drug effects/genetics
- Tumor Suppressor Protein p53/genetics
- X-Ray Microtomography
