Failure to Induce Apoptosis via BCL-2 Family Proteins Underlies Lack of Efficacy of Combined MEK and PI3K Inhibitors for KRAS-Mutant Lung Cancers

• Published in: Cancer research (Chicago, Ill.) Vol. 74; no. 11; pp. 3146 - 3156
• Main Authors: HATA, Aaron N, YEO, Alan, MINO-KENUDSON, Mari, WONG, Kwok-Kin, ENGELMAN, Jeffrey A, FABER, Anthony C, LIFSHITS, Eugene, ZHAO CHEN, CHENG, Katherine A, WALTON, Zandra, SAROSIEK, Kristopher A, LETAI, Anthony, HEIST, Rebecca S
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 01.06.2014
• Subjects: Animals; Antineoplastic agents; Apoptosis - drug effects; Apoptosis - genetics; Apoptosis Regulatory Proteins - genetics; Apoptosis Regulatory Proteins - metabolism; bcl-X Protein - genetics; bcl-X Protein - metabolism; Biological and medical sciences; Carcinoma, Non-Small-Cell Lung - drug therapy; Carcinoma, Non-Small-Cell Lung - genetics; Carcinoma, Non-Small-Cell Lung - metabolism; Cell Line, Tumor; Humans; Lung Neoplasms - drug therapy; Lung Neoplasms - genetics; Lung Neoplasms - metabolism; MAP Kinase Signaling System - drug effects; MAP Kinase Signaling System - genetics; Medical sciences; Mice; Mice, Nude; Mitochondria - drug effects; Mitochondria - genetics; Mitochondria - metabolism; Multiple tumors. Solid tumors. Tumors in childhood (general aspects); Mutation; Pharmacology. Drug treatments; Phosphatidylinositol 3-Kinases - genetics; Phosphatidylinositol 3-Kinases - metabolism; Phosphoinositide-3 Kinase Inhibitors; Pneumology; Protein Kinase Inhibitors - pharmacology; Proto-Oncogene Proteins c-bcl-2 - genetics; Proto-Oncogene Proteins c-bcl-2 - metabolism; ras Proteins - genetics; ras Proteins - metabolism; Signal Transduction - drug effects; Signal Transduction - genetics; Tumors; Tumors of the respiratory system and mediastinum; Lung disease; Enzyme; Respiratory disease; Transferases; Lung cancer; Treatment efficiency; Malignant tumor; Bronchopulmonary; Protein; 1-Phosphatidylinositol 3-kinase; K ras Gene; Cell death; C-Onc gene; Bronchus disease; Inhibitor; Mutation; Protooncogene; Cancer; Apoptosis
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.can-13-3728

Although several groups have demonstrated that concomitant use of MEK and phosphoinositide 3-kinase (PI3K) inhibitors (MEKi/PI3Ki) can induce dramatic tumor regressions in mouse models of KRAS-mutant non-small cell lung cancer (NSCLC), ongoing clinical trials investigating this strategy have been underwhelming to date. While efficacy may be hampered by a narrow therapeutic index, the contribution of biologic heterogeneity in the response of KRAS-mutant NSCLCs to MEKi/PI3Ki has been largely unexplored. In this study, we find that most human KRAS-mutant NSCLC cell lines fail to undergo marked apoptosis in response to MEKi/PI3Ki, which is key for tumor responsiveness in vivo. This heterogeneity of apoptotic response occurs despite relatively uniform induction of growth arrest. Using a targeted short hairpin RNA screen of BCL-2 family members, we identify BIM, PUMA, and BCL-XL as key regulators of the apoptotic response induced by MEKi/PI3Ki, with decreased expression of BIM and PUMA relative to BCL-XL in cell lines with intrinsic resistance. In addition, by modeling adaptive resistance to MEKi/PI3Ki both in vitro and in vivo, we find that, upon the development of resistance, tumors have a diminished apoptotic response due to downregulation of BIM and PUMA. These results suggest that the inability to induce apoptosis may limit the effectiveness of MEKi/PI3Ki for KRAS-mutant NSCLCs by contributing to intrinsic and adaptive resistance to this therapy.