Investigating mitochondrial networks as a critical determinant of response to antibody drug conjugates in advanced NSCLC

Project Summary The goal of this study is to evaluate mitochondrial networks as a critical determinant of response to antibody drug conjugates (ADCs) in advanced/metastatic (adv/met) non-small cell lung cancer (NSCLC). Recent advances with immune checkpoint inhibitors and targeted therapy have revolutionized the treatment of adv/met NSCLC, but most patients eventually develop therapy resistance. As such, novel approaches to the management of adv/met NSCLC are emerging, including three promising ADCs with the topoisomerase I (topo I) payload deruxtecan (DXd) that target HER2 (T-DXd), HER3 (HER3-DXd), and TROP2 (Dato-DXd). Importantly, recent data suggest that these three DXd-ADCs are effective in adv/met NSCLC after failure of standard therapies. Upon target receptor binding (HER2/HER3/TROP2), DXd-ADCs are internalized via receptor-mediated endocytosis, leading to cleavage of a plasma stable linker, selective delivery of the DXd payload, and DXd mediated tumor cell apoptosis. As such, it would be predicted that the efficacy of DXd-ADCs would be reliant upon high tumor target receptor expression assessed by IHC and expressed as an H-score. However, published data suggest that H-scores are unreliable predictors of patient response to DXd-ADCs and no clear understanding of the biological principles underlying NSCLC tumor response to these emerging agents exists. Apoptosis is the cytotoxic endpoint of the DXd payload, a process that is governed by mitochondria, and our preliminary data, generated via the novel structural/functional analysis that integrates positron emission tomography (PET) imaging with ultra-resolution microscopy, suggest that the structure and function of mitochondrial networks is mechanistically linked to DXd-ADC induced apoptosis. As such, we hypothesize that tumor intrinsic mitochondrial network structure and function dictate response/resistance to DXd-ADCs in NSCLC. To test this, Aim 1 will investigate baseline mitochondrial network architecture as a critical determinant of DXd- ADC response in NSCLC by profiling mitochondrial networks and cristae in cell lines, xenografts, patient-derived xenografts (PDXs), and tumor samples from DXd-ADC treated patients. In Aim 2, we will investigate mitochondrial network remodeling as a critical mechanism of DXd-ADC adaptive resistance, by quantitatively measuring changes in mitochondrial networks in cell lines, xenografts, PDXs, and primary patient tumors as DXd-ADC resistance occurs. Since most NSCLC patients do not respond to DXd-ADCs, quantitative profiling of mitochondrial networks has the potential to improve DXd-ADC patient outcomes by identifying conserved biological principles underlying treatment response.