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

University Of California Los Angeles, Los Angeles CA

Investigators

Abstract

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.