The Shimamura laboratory focuses on following three focus areas:
- Identification of new oncogenic drivers and therapeutic targets in lung cancer
- Identification of resistance mechanisms to targeted therapies in lung cancer
- Developing strategies to overcome resistance to targeted therapies in lung cancer
Project #1: Investigation of CXCR7 signaling in EGFR TKI resistant NSCLC
Although EGFR-targeted therapy significantly prolongs the survival of NSCLC patients with EGFR kinase domain activating mutations, acquired resistance to EGFR tyrosine kinase inhibitors (TKIs) poses a significant clinical problem. Recent clinical studies demonstrated that an increasing number of these resistant NSCLCs undergo epithelial to mesenchymal transition (EMT); however, the molecular basis of acquired EGFR TKI with an EMT phenotype remains elusive. Consequently, patients with the acquired resistance do not benefit from effective therapies. We have demonstrated that the inhibition of mutant EGFR in NSCLC promotes TGF beta1-mediated EMT. In patient specimens, C-X-C chemokine receptor type 7 (CXCR7) is significantly upregulated in acquired EGFR TKI resistant NSCLC cells with an EMT phenotype [Becker et al. 2019]. Prolonged depletion of CXCR7 with shRNA in the resistant cells not only restores epithelial phenotype but also sensitivity to EGFR TKIs. Our central hypothesis is that CXCR7 is a novel therapeutic target which promotes an EMT phenotype in EGFR mutant NSCLC and provides alternate survival/proliferation pathways when mutated-EGFR is inhibited. The overall objective is to determine the mechanism by which CXCR7 promotes EMT and thus resistance to EGFR TKI and determine whether CXCR7 is a superior drug target for NSCLC therapy.
In Aim 1, we will determine the mechanism by which CXCR7 promotes survival of EGFR TKI resistant NSCLC. For this aim, we will investigate if a ligand activation of CXCR7 is required for the engagement of the resistant phenotype. Additionally, we will evaluate therapeutic approaches using in vitro and in vivo models to suppress CXCR7 signaling to specifically target EMT-associated NSCLC cells with EGFR-TKI resistance.
In Aim 2, we will determine the therapeutic efficacy of targeting CXCR7 to eliminate EGFR TKI resistant cells with EMT. For this aim, we will investigate if EGFR TKI resistant cells with an EMT phenotype emerge through evolution from drug tolerant cells with increase expression of CXCR7 using PDX models and CXCR7 inhibitors. The results obtained from this proposal will facilitate the discovery of prognostic and therapeutic tools to inhibit CXCR7 expression leading to EGFR TKI resistance, to prevent the induction of EMT upon EGFR inhibition, and to provide a rationale to stratify NSCLC patients who become refractory to EGFR TKI with mesenchymal biomarkers for CXCR7-targeted therapeutics.
In Aim 3, we will determine mechanisms responsible for EMT regulation by CXCR7 in NSCLC. To this end, we will investigate how CXCR7 activates downstream transcription factors to support EMT in EGFR mutant NSCLC by using genomics and proteomics approaches, cell culture and complementary transgenic murine EGFR mutant NSCLC models.
Public Health Relevance
Although non-small cell lung cancer (NSCLC) patients with an activating EGFR mutation initially respond to EGFR tyrosine kinase inhibitors (TKIs), many patients succumb to acquired resistance, underscoring the need for improved therapeutic strategies especially for the increasing number of patients presenting with an epithelial- to-mesenchymal transition (EMT) phenotype. CXCR7 is a molecule that regulates both survival and an EMT phenotype of NSCLC cells resistant to EGFR TKIs. This proposal will uncover previously unknown activities of CXCR7 in NSCLC, which could lead to improved treatment options for patients with drug resistance with an EMT phenotype.
Project #2: Roles of EDN1 in NSCLC drug resistance
In lung cancer targeted therapy, responses to therapeutic agents are evaluated radiographically, with the assumption that drugs are efficiently distributed in the lung tumors as designed. Pharmacodynamic studies using fine needle aspirations of the lung tumors following treatments are not always done in parallel. Consequently, the image-based evaluation of the therapies makes no distinction between disease progression due to acquired resistance and insufficient drug distribution into tumors. In vivo pharmacodynamic and pharmacokinetic studies of drugs might not be done in tumors with drug intolerant populations of cells, called persisters, that may ultimately give rise to drug resistant cells. We found that a subset of drug tolerant EGFR mutant NSCLC cells secretes a potent vasoconstrictor, endothelin-1 (EDN1), to reduce the blood flow carrying drugs to the tumors [Pulido et al. 2020]. Therefore, we believe that FDA-approved endothelin receptor (EDNR) inhibitors used to treat pulmonary arterial hypertension can be safely used to improve the drug delivery to the tumors and therefore overall responses. Our central hypothesis is that the secretion of EDN1 from persister NSCLC cells promotes vasoconstriction in tumor-feeding blood vessels to decrease the blood flow and the delivery of therapeutic drugs to lung tumors. The overall objective is to evaluate if inhibiting the EDN1 – EDNR axis relieves the vasoconstriction to improve the drug penetrance in tumors. We will study the impact of EDN1 to the interactions between tumor and tumor microenvironment.
Public Health Relevance
In lung cancer targeted therapy, responses to therapeutic agents are evaluated radiographically or with CT, with the assumption that drugs penetrate the lung tumors efficiently as designed, therefore the image-based evaluation of the therapies does not distinguish between disease progression due to drug resistance or poor tumor penetration of the drugs being used. We have discovered that a subset of drug-treated NSCLC secretes a vasoconstrictor, endothelin-1, to limit the blood flow carrying drugs to the tumors. Therefore, the endothelin-1 receptor inhibitors used to treat pulmonary arterial hypertension can be safely repurposed to restore blood flow and ensure the efficient delivery of drugs to the tumors.
Project #3: Mechanisms of KRAS G12C inhibitor resistance
Julian Careterro, Ph.D. [University]
University of Valencia, Valencia, Spain
Agustin Lahoz, Ph.D. [LAB]
LaFe Hospital, Valencia Spain
Jeffrey A. Borgia, Ph.D. [LAB]
Rush University Medical Center, Chicago IL