Although there has been substantial progress in the understanding of the molecular biology and genetics of non-small cell lung cancer (NSCLC) over the last several years, metastatic NSCLC remains incurable, and patients suffering from this disease have a median survival of ~12 months. Recently, Epidermal Growth Factor Receptor (EGFR) tyrosine kinase inhibitors (TKIs), such as gefitinib and erlotinib, have demonstrated clinical activity in patients with NSCLC. A small subset of patients has activating mutations in the EGFR kinase domain. In these patients, TKIs can produce dramatic responses. In such situations, the cancer is """"""""addicted"""""""" to EGFR signaling. Such addicted cancers are unique in that the critical intracellular survival and growth signaling pathways such as phosphoinositide 3-kinase (PI3K) and extracellular signal-regulated kinase (ERK) are solely regulated by EGFR. Thus, when the cancer is treated with the EGFR TKI, both PI3K and ERK signaling are turned off and the cells undergo apoptosis and cell growth arrest. Although cancers with activating EGFR mutations often have dramatic responses to EGFR TKIs, these cancers invariably develop resistance (acquired resistance), thereby limiting the clinical benefit from these drugs. Recently, we and others have identified how some NSCLCs become resistant to EGFR inhibitors. These include a secondary mutation in EGFR, T790M, amplification of the MET oncogene, and activation of IGF1R. Interestingly, regardless of the specific mechanism, when the cancer becomes resistant to EGFR TKIs, there is re-activation of these critical downstream signaling pathways in the presence of the EGFR TKI. In contrast to the subset of NSCLCs with activating EGFR mutations, most NSCLCs do not demonstrate any initial response to EGFR TKIs (de novo or primary resistance). In particular, NSCLCs with KRAS mutations are especially resistant to EGFR TKIs. In these cancers, treatment with an EGFR TKI (or any TKI) does not lead to loss of PI3K and ERK signaling, and there is no detrimental affect on cell viability or growth. Furthermore, mutations in KRAS are the most common oncogenic mutations in NSCLCs (~25% of lung adenocarcinomas), and currently, there are no targeted therapies for this subset of cancers. However, in an effort to mirror the effects of a successful TKI treatment in these KRAS mutant cancers, we have been implementing a strategy that centers on simultaneously inhibiting PI3K and MEK by combining specific chemical inhibitors of each of these kinases. We have observed dramatic effects using this combination in vivo on genetically engineered mouse models of mutant Kras and EGFR driven lung cancers. Our preliminary data suggest that successful concomitant targeting of the PI3K and MEK pathways is feasible in mammals, and leads to dramatic tumor regression in mouse models of mutant KRas and EGFR driven lung cancers. This grant centers on developing this combination therapy using genetically engineered mouse models. We also aim to learn how cancers will become resistant to this therapy so we can proactively identify strategies to increase its efficacy and prolong benefit. We are hopeful that the studies proposed in this grant will serve as the foundation for successful clinical trials implementing this treatment strategy for patients with NSCLC.

Public Health Relevance

Understanding the roles of PI3K and MEK signaling pathways in the growth and survival of Kras and EGFR mutant lung cancers provide unique opportunities to identify rational combination targeted therapies for the treatment of this deadly disease and other types of cancer. Our proposal aims to characterize and evaluate the impact of novel therapeutic strategies that inhibit both the PI3K and MEK pathways in genetically defined de novo murine lung cancers. Results from the experiments proposed will help guide the clinical development of these combination therapies for patients with lung cancers and other cancer types.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
Project #
Application #
Study Section
Basic Mechanisms of Cancer Therapeutics Study Section (BMCT)
Program Officer
Forry, Suzanne L
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Dana-Farber Cancer Institute
United States
Zip Code
Deng, Jiehui; Wang, Eric S; Jenkins, Russell W et al. (2018) CDK4/6 Inhibition Augments Antitumor Immunity by Enhancing T-cell Activation. Cancer Discov 8:216-233
Li, Shuai; Liu, Shengwu; Deng, Jiehui et al. (2018) Assessing Therapeutic Efficacy of MEK Inhibition in a KRASG12C-Driven Mouse Model of Lung Cancer. Clin Cancer Res 24:4854-4864
Nabet, Behnam; Roberts, Justin M; Buckley, Dennis L et al. (2018) The dTAG system for immediate and target-specific protein degradation. Nat Chem Biol 14:431-441
Skoulidis, Ferdinandos; Goldberg, Michael E; Greenawalt, Danielle M et al. (2018) STK11/LKB1 Mutations and PD-1 Inhibitor Resistance in KRAS-Mutant Lung Adenocarcinoma. Cancer Discov 8:822-835
Liu, Shengwu; Li, Shuai; Hai, Josephine et al. (2018) Targeting HER2 Aberrations in Non-Small Cell Lung Cancer with Osimertinib. Clin Cancer Res 24:2594-2604
Wong, Gabrielle S; Zhou, Jin; Bin Liu, Jie et al. (2018) Author Correction: Targeting wild-type KRAS-amplified gastroesophageal cancer through combined MEK and SHP2 inhibition. Nat Med 24:1627
CaƱadas, Israel; Thummalapalli, Rohit; Kim, Jong Wook et al. (2018) Tumor innate immunity primed by specific interferon-stimulated endogenous retroviruses. Nat Med 24:1143-1150
Rusan, Maria; Li, Kapsok; Li, Yvonne et al. (2018) Suppression of Adaptive Responses to Targeted Cancer Therapy by Transcriptional Repression. Cancer Discov 8:59-73
Nangia, Varuna; Siddiqui, Faria M; Caenepeel, Sean et al. (2018) Exploiting MCL1 Dependency with Combination MEK + MCL1 Inhibitors Leads to Induction of Apoptosis and Tumor Regression in KRAS-Mutant Non-Small Cell Lung Cancer. Cancer Discov 8:1598-1613
Miao, Diana; Margolis, Claire A; Vokes, Natalie I et al. (2018) Genomic correlates of response to immune checkpoint blockade in microsatellite-stable solid tumors. Nat Genet 50:1271-1281

Showing the most recent 10 out of 108 publications