Project 3: The ATM Kinase as a Therapeutic Target in Drug Resistant NSCLC with Brain Metastasis

Yale University, New Haven CT

Investigators

Linked publications, trials & patents

Abstract

PROJECT SUMMARY Patients with non-small cell lung cancer (NSCLC) and multi-organ metastases have worst prognosis. NSCLC brain metastases remain challenging to treat, as they can progress despite initialing responding to blood-brain barrier (BBB) penetrant targeted therapies or immune checkpoint blockade (ICB). The ataxia- telangiectasia mutated serine/threonine kinase (ATM) is a canonical regulator of DNA damage response (DDR). However, ATM also controls redox homeostasis and inflammation, independently of the DDR. It is currently unclear which, if any, effector functions of ATM are necessary for drug resistance and metastasis in NSCLC. Our central hypothesis is that ATM is conditionally activated in late-stage NSCLC as an adaptive response to therapy and tumor microenvironment (TME) mediated stress. We also propose that inhibiting ATM using the BBB penetrant ATM kinase inhibitor AZD1390 will help delay or overcome resistance to standard of care treatments in certain NSCLC patients with metastases in the brain AND other sites. The premise of this proposal is based on our findings that ATM is activated in disseminated cancer cells from different models of NSCLC that are resistant to targeted therapy or ICB and that have metastasized to the brain. Moreover, we have shown that AZD1390 can improve the efficacy of targeted therapy and ICB in these models. Our mechanistic approach will leverage data-independent mass spectrometry (DIA-MS) to identify context dependent effectors and markers of ATM kinase activity and AZD1390 response. In Aim 1, we will use models of Epidermal Growth Factor Receptor mutant (EGFRmut) NSCLC that develop persistence or resistance to the tyrosine kinase inhibitor (TKI) osimertinib in vivo and test the hypothesis that reactive oxygen species (ROS) from the TME as well as cell intrinsic ROS induced by targeted therapies, lead to ATM activation. The requirement for ATM during progression in the brain will be compared to extracranial responses. In Aim 2, we will identify the mechanism by which ATM regulates tumor cell intrinsic immune evasion using novel immunogenic mouse models of Kirsten rat sarcoma virus mutant (KRASmut) NSCLCs, which develop brain metastases with concurrent systemic disease. We will ascertain the requirement for T cells, tumor associated macrophages, or microglia in mediating the synergistic effects of AZD1390 and ICB, and then corroborate our findings in human biospecimens, including brain metastasis tissue with matched extra-cranial tumors and liquid biopsies. Finally, in Aim 3, we will conduct a Phase Ib/II trial to evaluate the feasibility and efficacy of combining AZD1390 with osimertinib in patients with TKI resistant EGFRmut NSCLC including, but not limited to, cases with progressing brain metastases. Biopsies from patients that undergo standard of care surgery or that are enrolled in our trial will be leveraged to identify proteogenomic markers of AZD1390 response. Completion of the proposed Aims could reveal how to effectively treat extra-cranial tumors as well as brain metastases and improve the clinical outcomes of NSCLC patients with advanced stage disease.