Environmental Carcinogens Induce Minority MOMP to Initiate Carcinogenesis in Lung Cancer and Mesothelioma whileMaintaining Apoptotic Resistance via Mcl-1

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ABSTRACT / SUMMARY Lung cancer and mesothelioma accounted for over 200,000 new diagnoses in 2020. The common link between these cancers is chronic exposure to the known environmental carcinogens cigarette smoke and asbestos. They are difficult to treat because they typically harbor over 3000 mutations from the repeated insults from carcinogens. Targeting one mutation is circumvented through new mutations and bypass pathways. For this reason, targeting the mitochondrial pathways represents an important and novel approach because they are downstream of oncogenic driver proteins and pathway mutations. Recently, we have shown that chronic exposure of pre-neoplastic, Barrett’s esophageal cells to bile salt induced malignant transformation through a mechanism termed, ‘Minority MOMP (mitochondrial outer membrane permeabilization)’. MOMP is regulated by the B-cell lymphoma-2 (Bcl-2) family of proteins that are divided into pro- and anti-apoptotic proteins that interact at Bcl-2 homology-3 (BH3) domains. Minority MOMP partially activates the intrinsic pathway of the apoptotic machinery to levels that do not result in cell death but instead promote genomic instability, cellular transformation, and tumorigenesis. ‘Minority MOMP’ also resists apoptosis through the upregulation of the anti-apoptotic protein, Mcl-1. When we targeted Mcl-1, Minority MOMP shifted from the sub-lethal mitochondrial activation to frank apoptosis and the tumor cells died. What is not known is whether the Minority MOMP mechanism widely promotes malignant transformation from different environmental carcinogens (smoke and asbestos). Currently, the major obstacle in the treatment of thoracic cancers is overcoming resistance to therapy. If Minority MOMP is a common mechanism that promotes carcinogenesis while simultaneously enabling resistance to apoptosis, then disruption of Minority MOMP by targeting Bcl-2 proteins provides a therapeutic strategy to overcome treatment-refractory cancers. The goal is to determine whether ‘Minority MOMP’ is a generalizable, oncogenic mechanism associated with environmental carcinogens. We will determine whether this mechanism is associated with upregulation of clinically-targetable bcl-2 proteins. Normally, the oncogenic mitochondria enable cancer cell survival; if the sub- lethal activation of the apoptotic machinery is unchecked, the tumor cell will no longer resist apoptosis. These mitochondrial alterations should restore therapeutic susceptibility to treatment-refractory, thoracic cancers. Our hypothesis is that chronic exposure of environmental carcinogens induces both carcinogenesis and resistance to apoptosis through Minority MOMP. If Minority MOMP is an oncogenic mechanism that requires upregulation of anti-apoptotic proteins for cancer cell survival, then shifting Minority MOMP to apoptosis by blocking the compensatory anti-apoptotic proteins provides a novel and clinically-actionable treatment strategy.