DNA repair pathway inhibitors are a new class of anticancer drugs that are advancing in clinical trials. Peposertib is an inhibitor of DNA-dependent protein kinase (DNA-PK), which is a key driver of nonhomologous end-joining (NHEJ). To identify regulators of response to peposertib, we performed a genome-wide CRISPR knockout screen and found that loss of POLQ (polymerase theta, POLθ) and other genes in the microhomology-mediated end-joining (MMEJ) pathway are key predictors of sensitivity to DNA-PK inhibition. Simultaneous disruption of two DNA repair pathways via combined treatment with peposertib plus a POLθ inhibitor novobiocin exhibited synergistic synthetic lethality resulting from accumulation of toxic levels of DNA double-strand break end resection. TP53-mutant tumor cells were resistant to peposertib but maintained elevated expression of POLQ and increased sensitivity to novobiocin. Consequently, the combination of peposertib plus novobiocin resulted in synthetic lethality in TP53-deficient tumor cell lines, organoid cultures, and patient-derived xenograft models. Thus, the combination of a targeted DNA-PK/NHEJ inhibitor with a targeted POLθ/MMEJ inhibitor may provide a rational treatment strategy for TP53-mutant solid tumors. Significance: Combined inhibition of NHEJ and MMEJ using two nontoxic, targeted DNA repair inhibitors can effectively induce toxic DNA damage to treat TP53-deficient cancers.

Mean heart dose (MHD) over 10 Gy and left anterior descending (LAD) coronary artery volume (V) receiving 15 Gy (V15Gy) greater than 10% can significantly increase the risk of major adverse cardiac events (MACE) in patients with non-small cell lung cancer (NSCLC). We sought to characterize the discordance between MHD and LAD dose and the association of this classification on the risk of MACE following radiotherapy. Retrospective analysis of 701 patients with locally advanced NSCLC treated with radiotherapy. Coefficient of determination for MHD and LAD V15Gy was calculated. Four groups were defined based on high or low MHD (≥10 Gy vs. <10 Gy) and LAD V15Gy (≥10% vs. <10%). MACE (unstable angina, heart failure, myocardial infarction, coronary revascularization, and cardiac death) cumulative incidence was estimated and Fine and Gray regressions performed. The proportion of variance in LAD V15Gy predictable from MHD was only 54.5% (R2=0.545). There was discordance (where MHD was high [≥10 Gy] and LAD low [V15Gy <10%], or vice versa), in 23.1% (n=162). 2-year MACE estimates were: 4.2% (MHDhigh/LADlow), 7.6% (MHDhigh/LADhigh), 1.8% (MHDlow/LADlow), and 13.0% (MHDlow/LADhigh). Adjusting for pre-existing coronary heart disease and other prognostic factors, MHDhigh/LADlow (subdistribution hazard ratio [SHR] 0.34; 95%CI: 0.13-0.93;P=.036) and MHDlow/LCAlow (SHR 0.24; 95%CI: 0.10-0.53;P<.001) were associated with a significantly reduced risk of MACE. MHD is insufficient to predict LAD V15Gy with confidence. When MHD and LAD V15Gy dose exposure is discordant, isolated low LAD V15Gy significantly reduces the risk of MACE in patients with locally advanced NSCLC following radiotherapy, suggesting that the validity of whole heart metrics for optimally predicting cardiac events should be reassessed.

To identify genes whose loss confers resistance to CHK1 inhibitors, we perform genome-wide CRISPR-Cas9 screens in non-small-cell lung cancer (NSCLC) cell lines treated with the CHK1 inhibitor prexasertib (CHK1i). Five of the top six hits of the screens, MYBL2 (B-MYB), LIN54, FOXM1, cyclin A2 (CCNA2), and CDC25B, are cell-cycle-regulated genes that contribute to entry into mitosis. Knockout of MMB-FOXM1 complex components LIN54 and FOXM1 reduce CHK1i-induced DNA replication stress markers and premature mitosis during Late S phase. Activation of a feedback loop between the MMB-FOXM1 complex and CDK1 is required for CHK1i-induced premature mitosis in Late S phase and subsequent replication catastrophe, indicating that dysregulation of the S to M transition is necessary for CHK1 inhibitor sensitivity. These findings provide mechanistic insights into small molecule inhibitors currently studied in clinical trials and provide rationale for combination therapies.

PURPOSE: NRG Oncology/Alliance LU005 (ClinicalTrials.gov identifier: NCT03811002 ) tested the addition of atezolizumab to concurrent chemoradiation (CRT) in this open-label, phase III international trial. METHODS: Patients with limited-stage small cell lung cancer (LS-SCLC), stage Tx-IV, N0-3, and M0 with Eastern Cooperative Group performance status (PS) 0-2 received one cycle of chemotherapy (platinum/etoposide) before study registration and were randomly assigned to CRT alone versus CRT plus concurrent and adjuvant atezolizumab, 1,200 mg once daily, every 3 weeks until investigator-assessed progression or intolerable side effects for a maximum of 17 cycles. Patients were stratified by choice of chemotherapy (cisplatin v carboplatin), radiation fractionation schedule (66 Gy once daily v 45 Gy twice daily), sex, and PS (0/1 v 2). The primary end point was overall survival (OS). Secondary end points included investigator-assessed progression-free survival (PFS), objective response rate, local control, and distant-metastasis-free survival (DMFS). RESULTS: patients were randomly assigned from May 2019 to December 2023. The median OS was 36.1 months (95% CI, 28.1 to 42.5) for the CRT-alone arm and 31.1 months (95% CI, 28.5 to 44.7) for the CRT + atezolizumab arm, respectively (hazard ratio [HR], 1.03 [95% CI, 0.80 to 1.32]). The median PFS was 11.4 months (95% CI, 10.3 to 13.2) for the CRT-alone arm and 12.1 months (95% CI, 10.9 to 15.2) for the CRT + atezolizumab arm, respectively (HR, 0.98 [95% CI, 0.79 to 1.22]). The median DMFS was 13.0 months (95% CI, 11.3 to 18.2) for the CRT-alone arm and 16.8 months (95% CI, 12.1 to 21.6) for the CRT + atezolizumab arm (HR, 0.96 [95% CI, 0.76 to 1.21]). No unexpected safety signals with concurrent atezolizumab were observed. CONCLUSION: Concurrent and adjuvant atezolizumab with chemoradiation did not improve survival in patients with LS-SCLC.

PURPOSE: Stereotactic radiation (SRS/SRT) as opposed to whole-brain radiation (WBRT) represents the standard of care for patients with a limited number of brain metastases given the relatively favorable toxicity profile associated with stereotactic treatment. However, in patients with small cell lung cancer (SCLC), WBRT remains standard because of a lack of prospective data supporting SRS/SRT and concerns related to intracranial progression and neurologic death when WBRT is omitted. We conducted a single-arm, multicenter, phase II trial of SRS/SRT in patients with SCLC and 1-10 brain metastases to assess neurologic death rates relative to historical controls managed with WBRT (ClinicalTrials.gov identifier: NCT03391362 ). METHODS: Patients were eligible if they had SCLC or an extrathoracic small cell primary and 1-10 brain metastases. Previous brain-directed radiation including prophylactic cranial irradiation was not permitted. Neurologic death was defined as marked, progressive, radiographic brain progression accompanied by corresponding neurologic symptomatology without systemic disease progression or systemic symptoms of a life-threatening nature. Close imaging-based surveillance of the brain post-SRS/SRT was used. RESULTS: Between February 2018 and April 2023, 100 patients were enrolled. The median number of brain metastases was 2 (IQR, 1-4; range, 1-10). The median overall survival was 10.2 months; only 22% of patients required salvage WBRT. In total, 20 neurologic deaths were observed, relative to 64 non-neurologic deaths. The neurologic death rate at 1 year was 11.0% (95% CI, 5.8 to 18.1); the historical rate in patients managed with WBRT was 17.5%. CONCLUSION: Our prospective, multi-institutional study demonstrated low rates of neurologic death when SRS/SRT as opposed to WBRT is used in patients with SCLC and 1-10 brain metastases who are surveilled closely post-treatment, supporting the utility of stereotactic approaches in this population.

PURPOSE: Coronary artery calcium (CAC) quantified on computed tomography (CT) scans is a robust predictor of atherosclerotic coronary disease; however, the feasibility and relevance of quantitating CAC from lung cancer radiotherapy planning CT scans is unknown. We used a previously validated deep learning (DL) model to assess whether CAC is a predictor of all-cause mortality and major adverse cardiac events (MACEs).METHODS: Retrospective analysis of non–contrast-enhanced radiotherapy planning CT scans from 428 patients with locally advanced lung cancer is performed. The DL-CAC algorithm was previously trained on 1,636 cardiac-gated CT scans and tested on four clinical trial cohorts. Plaques ≥ 1 cubic millimeter were measured to generate an Agatston-like DL-CAC score and grouped as DL-CAC = 0 (very low risk) and DL-CAC ≥ 1 (elevated risk). Cox and Fine and Gray regressions were adjusted for lung cancer and cardiovascular factors.RESULTS: The median follow-up was 18.1 months. The majority (61.4%) had a DL-CAC ≥ 1. There was an increased risk of all-cause mortality with DL-CAC ≥ 1 versus DL-CAC = 0 (adjusted hazard ratio, 1.51; 95% CI, 1.01 to 2.26; P = .04), with 2-year estimates of 56.2% versus 45.4%, respectively. There was a trend toward increased risk of major adverse cardiac events with DL-CAC ≥ 1 versus DL-CAC = 0 (hazard ratio, 1.80; 95% CI, 0.87 to 3.74; P = .11), with 2-year estimates of 7.3% versus 1.2%, respectively.CONCLUSION: In this proof-of-concept study, CAC was effectively measured from routinely acquired radiotherapy planning CT scans using an automated model. Elevated CAC, as predicted by the DL model, was associated with an increased risk of mortality, suggesting a potential benefit for automated cardiac risk screening before cancer therapy begins.