Predictive biomarkers and combination strategies to overcome resistance to HER2- and TROP2-directed antibody drug conjugates with topoisomerase I inhibitor payloads in SCLC

Treatment-naïve small cell lung cancer (SCLC) is highly sensitive to frontline chemotherapy; however relapsed SCLC acquires broad chemoresistance that renders conventional second line agents like topotecan, a topoisomerase inhibitor (TOP1i), largely ineffective. Recent clinical trials with surface targeting strategies such as antibody drug conjugates (ADCs) with TOP1i-based payloads have demonstrated strong responses in relapsed small SCLC. Identifying biomarkers of response and resistance to these agents will be important to optimize the effectiveness of this new therapeutic class. We previously showed that non-neuroendocrine SCLC tumors express low levels of DLL3 and SEZ6 , but high levels of TACSTD2 (TROP2) and ERBB2 (HER2). In this study, we examined the activities of different HER2- and TROP2-directed ADCs with TOP1i- and non-TOP1i-based payloads in SCLC cell lines. While target expression did not correlate with ADC sensitivity, SCLC cell lines with high SLFN11 levels showed greater sensitivity to TOP1i-based HER2- and TROP2-ADCs and their payloads. SLFN11 knockdown confirmed that SLFN11 loss reduces ADC sensitivity. Notably, combination with an ATR inhibitor sensitized resistant SLFN11-low SCLC cell lines to TOP1i-based ADCs. In contrast, sensitivity to a non-TOP1i-based HER2 ADC was not associated with SLFN11 expression. High cMYC and ABCB1 (P-glycoprotein) levels were also associated with resistance to TOP1i-based ADC, but not to non-TOP1i ADCs. Mechanistically, TOP1i-based HER2- and TROP2-ADCs induced significant DNA damage and apoptosis. Increases in PDL-1 expression, STING-chemokine CCL5, along with extracellular ATP were also detected, indicating induction of immunogenic responses and supporting combinations with immunotherapy. Overall, these results identify SLFN11 as a clinical biomarker for patient selection and provide preclinical support for combinations with ATR inhibitor or using alternate non-TOP1i-based ADCs to overcome resistance to TOP1i-based HER2- and TROP2-ADCs.