Induced Degradation of Lineage-specific Oncoproteins Drives the Selective PARP1 Inhibitor Toxicity in Small Cell Lung Cancer

Abstract

A subset of small cell lung cancer (SCLC) shows clinically relevant response to PARP1 inhibitors (PARPi). However, BRCA1/2 mutations are not commonly found in SCLC, and the underlying mechanism(s) of PARPi sensitivity in SCLC is poorly understood. We performed quantitative proteomic analyses and identified proteomic changes that signify PARPi responses in a large panel of molecularly annotated patient-derived SCLC lines. We found that the toxicity of PARPi in SCLC could be explained, at least in part, by the PARPi-induced degradation of key lineage-specific oncoproteins including ASCL1, NEUROD1, POU2F3, KDM4A, and KDM5B. Importantly, the degradation of these SCLC lineage-specific oncoproteins could also be induced by commonly used chemotherapeutic agents. Biochemical experiments showed that PARPi-induced activation of E3 ligases (e.g., HUWE1 and RNF8) mediated the ubiquitin-proteasome system (UPS)-dependent degradation of these oncoproteins. Interestingly, although PARPi resulted in a general DNA damage response in SCLC cells, this signal is sensed by different SCLC cell lines to generate a cell-specific response. The dissection of the cell-specific oncoprotein degradation response led to the identification of potentially predictive biomarkers for PARPi in SCLC. The combination of PARPi and agents targeting these pathways led to dramatically improved cytotoxicity in SCLC. PARPi-induced degradation of lineage-specific oncoproteins therefore represents a novel mechanism to explain the efficacy of PARPi in tumors without BRCA1/2 mutations. HighlightsO_LIQuantitative mass spectrometric analysis identifies proteomic changes associated with PARPi treatment in a large panel of SCLC cell lines. C_LIO_LIPARPi leads to the degradation of lineage-specific oncoproteins (e.g., ASCL1 and KDM4A) via the DNA damage responsive E3 ubiquitin ligases (e.g., HUWE1 and RNF8). C_LIO_LIA combination of PARPi and agents targeting the lineage-specific oncoproteins offers a more complete and durable therapeutic response in SCLC, compared to PARPi alone. C_LIO_LIExpression of lineage-specific oncoproteins and the associated ubiquitination machinery are predictive biomarkers for PARPi-induced cytotoxicity in SCLC. C_LI