Somatic activating mutations in the kinase domain of the epidermal growth factor receptor (EGFR) drive the growth of 10-20% of non-small cell lung cancers (NSCLCs), the leading cause of cancer mortality1,2. EGFR tyrosine kinase inhibitors (TKIs) are effective in many EGFR-mutant NSCLC patients1,2. However, this clinical efficacy is limited by innate, adaptive, and acquired EGFR TKI resistance that prevents long-term patient survival3-6. Identifying the mechanisms that limit EGFR TKI response is essential to improve clinical outcomes. When EGFR-mutant patients do respond to initial EGFR TKI treatment, the responses are typically incomplete because some tumor cells persist and survive as residual disease through poorly understood mechanisms5,7-10. These residual disease cells form a reservoir of EGFR TKI-tolerant cells that eventually grow to cause acquired resistance. There is an urgent need to define the molecular events that allow these EGFR-mutant tumor cells to persist as residual disease during initial EGFR TKI treatment in order to design therapeutic strategies to intercept this process and thereby improve the magnitude and duration of EGFR TKI response in patients. From its inception, the goals of this project have been to: (a) understand the mechanism(s) by which NF-kB limits EGFR TKI response and (b) identify a small molecule inhibitor of NF-kB that can effectively and safely enhance EGFR TKI response in EGFR-mutant NSCLC. In ongoing studies funded by this project, we have made progress towards achieving these goals7,11-20. Our initial studies demonstrated NF-kB is a promising target to overcome innate and prevent acquired EGFR TKI resistance, through experiments that revealed a novel role for EGFR TKI-induced adaptive activation of NF-kB in driving incomplete response and the residual disease that is a prelude to acquired resistance. We showed the novel direct NF-kB inhibitor, PBS-1086, can be combined safely with an EGFR TKI to enhance response, suppress residual disease, and prevent acquired resistance in preclinical EGFR-mutant NSCLC cellular and animal models7. Based on our work, PBS-1086 is undergoing clinical development. We now seek to extend this project in novel directions to dissect the mechanism by which NF-kB mediates tolerance to EGFR TKI treatment to promote the residual disease that fuels acquired resistance. We will test the innovative hypothesis that NF-kB drives unexplained and emerging features of drug-tolerant persister cells during EGFR TKI treatment: (1) apoptotic resistance (Aim 1) and (2) de novo gain of EGFR TKI resistance mutations (Aim 2)7-9,21. These persister cell features arising via NF-kB activation could be mutually reinforcing by simultaneously enabling tumor cell plasticity, survival, and genetic adaptation to promote the evolution of EGFR TKI resistance. We are pursuing a long-term strategy to define the function of NF-kB in limiting response to EGFR TKI treatment to guide future efforts to rationally deploy inhibitors of NF-kB signaling or of its key targets in order to better constrain the evolution of resistance and improve clinical outcomes.
. Lung cancer is a major public health problem because it is the most common cause of cancer-related death in the US. Treatments that specifically target proteins that drive lung cancer growth, such as EGFR inhibitors, are leading to improved responses in lung cancer patients but success is limited because treatment resistance occurs. The studies in this grant proposal focus on the discovery of new mechanisms of resistance to EGFR inhibitors in lung cancer. Findings from our studies will hopefully lead to improved treatments that overcome resistance to EGFR inhibitors by allowing for the design of rational combination therapies. Our findings will have a major impact on lung cancer by optimizing personalized treatment strategies that will increase the survival of lung cancer patients.
|Neel, Dana S; Allegakoen, David V; Olivas, Victor et al. (2018) Differential subcellular localization regulates oncogenic signaling by ROS1 kinase fusion proteins. Cancer Res :|
|McCoach, Caroline E; Bivona, Trever G (2018) The evolving understanding of immunoediting and the clinical impact of immune escape. J Thorac Dis 10:1248-1252|
|Bugaj, L J; Sabnis, A J; Mitchell, A et al. (2018) Cancer mutations and targeted drugs can disrupt dynamic signal encoding by the Ras-Erk pathway. Science 361:|
|Zaman, Aubhishek; Bivona, Trever G (2018) Emerging application of genomics-guided therapeutics in personalized lung cancer treatment. Ann Transl Med 6:160|
|Gong, Ke; Guo, Gao; Gerber, David E et al. (2018) TNF-driven adaptive response mediates resistance to EGFR inhibition in lung cancer. J Clin Invest 128:2500-2518|
|Nichols, Robert J; Haderk, Franziska; Stahlhut, Carlos et al. (2018) RAS nucleotide cycling underlies the SHP2 phosphatase dependence of mutant BRAF-, NF1- and RAS-driven cancers. Nat Cell Biol 20:1064-1073|
|Neel, Dana S; Bivona, Trever G (2017) Resistance is futile: overcoming resistance to targeted therapies in lung adenocarcinoma. NPJ Precis Oncol 1:|
|Blakely, Collin M; Watkins, Thomas B K; Wu, Wei et al. (2017) Evolution and clinical impact of co-occurring genetic alterations in advanced-stage EGFR-mutant lung cancers. Nat Genet 49:1693-1704|
|Jacobsen, Kirstine; Bertran-Alamillo, Jordi; Molina, Miguel Angel et al. (2017) Convergent Akt activation drives acquired EGFR inhibitor resistance in lung cancer. Nat Commun 8:410|
|Hockenberry, Marilyn J; Hooke, Mary C; Rodgers, Cheryl et al. (2017) Symptom Trajectories in Children Receiving Treatment for Leukemia: A Latent Class Growth Analysis With Multitrajectory Modeling. J Pain Symptom Manage 54:1-8|
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