Ritsu Ibusuki

EGFR tyrosine kinase inhibitors (TKIs) are effective against EGFR-mutated lung cancer, but tumors eventually develop resistance to these drugs. Although TP53 gain-of-function (GOF) mutations promote carcinogenesis, their effect on EGFR-TKI efficacy has remained unclear. We here established EGFR-mutated lung cancer cell lines that express wild-type (WT) or various mutant p53 proteins with CRISPR-Cas9 technology and found that TP53-GOF mutations promote early development of resistance to the EGFR-TKI osimertinib associated with sustained activation of ERK and expression of c-Myc. Gene expression analysis revealed that osimertinib activates TNF-α-NF-κB signaling specifically in TP53-GOF mutant cells. In such cells, osimertinib promoted interaction of p53 with the NF-κB subunit p65, translocation of the resulting complex to the nucleus and its binding to the TNF promoter, and TNF-α production. Concurrent treatment of TP53-GOF mutant cells with the TNF-α inhibitor infliximab suppressed acquisition of osimertinib resistance as well as restored osimertinib sensitivity in resistant cells in association with attenuation of ERK activation and c-Myc expression. Our findings indicate that induction of TNF-α expression by osimertinib in TP53-GOF mutant cells contributes to the early development of osimertinib resistance, and that TNF-α inhibition may therefore be an effective strategy to overcome such resistance in EGFR-mutant lung cancer with TP53-GOF mutations.

BACKGROUND: We investigated the measurement of end-tidal partial pressure of carbon dioxide (P ETCO 2 ) with a capnometer in patients with respiratory failure, and we determined whether this technique could provide an alternative to measurement of P aCO 2 using arterial blood gas analysis in the clinical setting. METHODS: We measured P ETCO 2 in subjects with hypoxemic and hypercarbic respiratory failure using a capnometer. We simultaneously measured P aCO 2 , venous partial pressure of carbon dioxide (P v̄CO 2 ), and transcutaneously measured partial pressure P CO 2 (P tcCO 2 ). We analyzed agreements among these parameters with Bland-Altman analysis. We obtained 30 samples from subjects with hypoxemic respiratory failure and 30 samples from subjects with hypercarbic respiratory failure. RESULTS: Thirty subjects with hypoxemic respiratory failure and 18 subjects with hypercarbic respiratory failure participated in this study. Significant relationships were found between P ETCO 2 and P aCO 2 , between P tcCO 2 and P aCO 2 , and between P v̄CO 2 and P aCO 2 . Bland-Altman analysis of P ETCO 2 and P aCO 2 in all subjects revealed a bias of 6.48 mm Hg (95% CI 4.93–8.03, P < .001) with a precision of 6.01 mm Hg. Bland-Altman analysis of P ETCO 2 and P aCO 2 with hypoxemic respiratory failure revealed a bias of 5.14 mm Hg (95% CI 3.35–6.93, P < .001) with a precision of 4.80 mm Hg. Bland-Altman analysis of P ETCO 2 and P aCO 2 in subjects with hypercarbic respiratory failure revealed a bias of 7.83 mm Hg (95% CI 5.27–10.38, P < .001) with a precision of 6.83 mm Hg. CONCLUSIONS: P ETCO 2 can be measured simply using a capnometer, and P ETCO 2 measurements can estimate P aCO 2 . However, the limits of agreement were wide. Therefore, care providers must pay attention to the characteristics and errors of these devices. These results suggest that measurement of P ETCO 2 might be useful for screening for hypercarbic respiratory failure in the clinical setting.

Background: Thyroid transcription factor-1 (TTF-1) expression in advanced non-squamous non-small cell lung cancer (NSCLC) has been associated with the efficacy of pemetrexed plus platinum chemotherapy. However, the relation between TTF-1 expression and efficacy of the combination of programmed cell death 1 (PD-1)/programmed cell death ligand 1 (PD-L1) inhibitors plus pemetrexed and platinum chemotherapy, a standard first-line treatment regimen for advanced non-squamous NSCLC, has remained unclear. Methods: We retrospectively evaluated TTF-1 expression in tumor tissue of patients with advanced or recurrent non-squamous NSCLC treated with PD-1/PD-L1 inhibitors plus pemetrexed and platinum chemotherapy in the first-line setting. Clinical characteristics and pathological data for each patient were assessed, and progression-free survival (PFS) was evaluated. Bias due to patient background was minimized by application of inverse probability of treatment weighting (IPTW) analysis. Results: A total of 122 patients, 75 (61.5%) of whom were positive for TTF-1 immunostaining in tumor specimens, was included in this multicenter study. At the time of analysis, 89 (73.0%) patients had experienced progression events and 44 (36.1%) had died [median follow-up 14.6 months (range, 0.53–29.5 months)]. PFS was longer for TTF-1-positive patients than for TTF-1-negative patients [median, 12.2 vs. 6.0 months; hazard ratio (HR) =0.63 (95% CI: 0.37–1.06); log-rank P=0.028]. IPTW-adjusted PFS was significantly longer for TTF-1-positive than for TTF-1–negative patients [HR =0.62 (95% CI: 0.46–0.83); log-rank P=0.024]. Conclusions: TTF-1 expression in advanced non-squamous NSCLC can serve as a basis for prediction of PFS in patients treated with PD-1/PD-L1 inhibitors plus pemetrexed and platinum chemotherapy in the first-line setting.

BACKGROUND: The Oncomine Dx Target Test Multi-CDx System (ODxTT) is a next-generation sequencing panel approved as a companion diagnostic for drugs targeted to corresponding gene alterations in non-small cell lung cancer. However, appropriate slide conditions for ODxTT have remained unclear. METHODS: We focused on the production of the number of tumor cells on a formalin-fixed paraffin-embedded (FFPE) section and the number of prepared slides, designated the TS value, and determined a TS value of ≥4000 as a target slide condition for ODxTT. We evaluated the impact of this condition on ODxTT testing with tumor specimens found to have a TS of <4000 (n = 23) or a TS of ≥4000 (n = 142). RESULTS: A positive correlation was apparent between the TS value and the concentrations of both DNA and RNA. Among the 142 samples with a TS of ≥4000, a sufficient concentration of DNA or RNA for ODxTT analysis was achieved in 100% and 98% samples, respectively. Among samples explored for driver gene alterations after determination of the target slide condition (TS ≥4000), most (84.9%) had a TS of ≥4000 and were submitted for ODxTT analysis. CONCLUSION: Our findings indicate that a TS of ≥4000 is a feasible and relevant criterion for ODxTT testing, and its adoption should help to improve the success rate of such testing in clinical practice.