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Programmed cell death protein ligand‐1 (PD‐L1) expression in non‐small cell lung cancer (NSCLC) tumors guides treatment selection. PD‐L1 expression in circulating tumor cells (CTCs) may provide further information. We have explored PD‐L1 and marker of proliferation Ki‐67 (Ki67; also known as MKI67) in CTCs in longitudinal samples of 47 advanced NSCLC patients receiving pembrolizumab. A triple immunofluorescence, against cytokeratin, PD‐L1, and Ki67, was performed on peripheral blood mononuclear cells, at baseline, post‐first cycle, post‐third, and primary resistance (PMR). Patients displaying PMR (progression at first evaluation) were classified as progressive disease (PD) and those with clinical benefit as disease control (DC). CTCs were categorized as PD‐L1high/low/medium/negative and Ki67+ or Ki67−. CTC evaluation revealed a significant increase in the PD‐L1low CTC rate at PMR compared to baseline (2.5% at baseline vs. 36.5% at PMR), whereas a reduction in the PD‐L1high CTC rate was observed (31.5% vs. 0%, respectively). Investigation of CTC status between PD and DC patients showed that PD patients more frequently increased total and PD‐L1low CTCs after first cycle compared to DC (83% of PD vs. 37% of DC and 67% of PD vs. 8% of DC, respectively). Progression‐free survival (PFS) was longer in patients with decreased total and PD‐L1low CTCs after first cycle compared to those with increased CTCs (median PFS: not reached vs. 2 months). PD‐L1+ patients presenting a high Ki67 index (% Ki67+ CTCs > 30%) before treatment had a shorter PFS compared to those with a low Ki67 (≤ 30%), and overall survival (OS) was shorter in PD‐L1+ patients harboring Ki67+ CTCs compared to those not presenting (median OS: 11.8 months vs. 33.1 months, respectively). In sequential samples of patients with a durable benefit, a low Ki67 index was observed. Our results suggest that monitoring PD‐L1 and Ki67 expression in CTCs of NSCLC patients treated with pembrolizumab may be predictive for pembrolizumab efficacy.

Abstract Drug resistance severely limits the clinical therapeutic value of molecularly targeted drugs. Growth factors gain a tremendous amount of focus due to the ability to promote drug resistance in non‐small‐cell lung cancer (NSCLC). However, whether tumor cells themselves can mediate drug resistance by secreting growth factors needs further clarification. Here, we first screened growth factors to identify autocrine epidermal growth factor (EGF) and transforming growth factor alpha (TGF‐α) that caused primary resistance to the ALK inhibitor TAE684 in H3122 cells and the c‐MET‐specific inhibitor SGX‐523 in EBC‐1 cells. Next, we discovered increased autocrine production of EGF and TGF‐α in established acquired resistant H3122/TR and EBC‐1/SR cells. Importantly, overexpression of EGF and TGF‐α in two NSCLC cell lines produced resistance to TAE684 and SGX‐523. Clinically, NSCLC patients with high expression of EGF and TGF‐α developed primary resistance to crizotinib. Mechanistically, autocrine EGF and TGF‐α activated EGFR signaling pathways to survive targeted c‐Met and ALK inhibition. Furthermore, combined treatment with gefitinib circumvented EGF‐ and TGF‐α‐mediated primary and acquired resistance to TAE684/SGX‐523. Taken together, these results suggested increased autocrine EGF and TGF‐α conferred primary and acquired resistance to ALK/c‐Met kinase inhibitors in NSCLC.

Epidermal growth factor receptor (EGFR) mutation‐positive non‐small cell lung cancer (NSCLC) patients benefit from EGFR tyrosine kinase inhibitors (TKIs), while some patients demonstrate a resistance to EGFR‐TKIs. In the case reported here, the NSCLC patient harboring an EGFR‐sensitive mutation and YES1 amplification was treated with afatinib as first‐line therapy, but was found to have progressive disease four weeks later. During subsequent chemotherapy, this patient's disease progressed rapidly. Mechanisms of primary resistance to EGFR‐TKIs remain unclear. This case suggested that YES1 amplification might be associated with primary resistance to EGFR‐TKIs and YES1 amplification might be a negative predictor of EGFR‐TKI treatment in NSCLC patients harboring EGFR sensitive mutations.

EGFR‐activating mutations have been recognized as the most important predictor of response to EGFR‐tyrosine kinase inhibitors (TKIs); however, 20–30% of patients harboring EGFR‐activating mutations show poor responses. The mechanisms of such EGFR‐TKI primary resistance are still poorly understood. In our case, a non‐small cell lung cancer patient developed intrinsic EGFR‐TKI resistance and was then confirmed to simultaneously harbor an L858R mutation and ROS1 rearrangement. Salvage chemotherapy plus Endostar showed enduring therapeutic effects, achieving a disease‐free survival period of 24 months and overall survival of 30 months. This suggests that co‐activation of different oncogenic signal pathways might be a potential mechanism of EGFR‐TKI primary resistance. Chemotherapy combined with anti‐angiogenesis should be considered an important salvage strategy. Further studies are warranted to verify these findings and explore the underlying mechanisms involved.

Current National Comprehensive Cancer Network (NCCN) guidelines suggest plasma‐based testing (liquid biopsy) for T790M in epidermal growth factor receptor (EGFR)‐mutated non‐small cell lung carcinoma (NSCLC) with acquired resistance to first‐/second‐generation EGFR tyrosine kinase inhibitors (TKIs). Positivity for resistant mutation on liquid biopsy may obviate the need for invasive tissue biopsy. We report a rare case of primary resistance to osimertinib, although liquid biopsy revealed EGFR T790M positivity. A 63‐year‐old male, never smoker, was diagnosed with stage IV lung adenocarcinoma with EGFR exon 19 deletion. Treatment started with erlotinib and was continued for 15 months until disease progression. Osimertinib was initiated when liquid biopsy showed EGFR T790M positivity. However, primary resistance to osimertinib was noted on follow‐up imaging. Re‐biopsy revealed small cell lung cancer. Detection of T790M via liquid biopsy among NSCLC patients with acquired resistance to EGFR‐TKI might miss other possible resistant mechanisms. Tissue biopsy should be considered to exclude small cell lung carcinoma (SCLC) transformation.

Abstract Hepatocellular carcinoma (HCC) is the malignancy derived from normal hepatocytes with increasing incidence and extremely poor prognosis worldwide. The only approved first‐line systematic treatment agent for HCC, sorafenib, is capable to effectively improve advanced HCC patients’ survival. However, it is gradually recognized that the therapeutic response to sorafenib could be drastically diminished after short‐term treatment, defined as primary resistance. The present study is aimed to explore the role of stress‐inducible protein Sestrin2 (SESN2), one of the most important sestrins family members, in sorafenib primary resistance. Herein, we initially found that SESN2 expression was significantly up‐regulated in both HCC cell lines and tissues compared to normal human hepatocytes and corresponding adjacent liver tissues, respectively. In addition, SESN2 expression was highly correlated with sorafenib IC50 of HCC cell lines. Thereafter, we showed that sorafenib treatment resulted in an increase of SESN2 expression and the knockdown of SESN2 exacerbated sorafenib‐induced proliferation inhibition and cell apoptosis. Further mechanistic study uncovered that SESN2 deficiency impaired both AKT and AMPK phosphorylation and activation after sorafenib treatment. Moreover, the correlations between SESN2 expression and both phosphor‐AKT and phosphor‐AMPK expression were illustrated in HCC tissues. Taken together, our study demonstrates that SESN2 activates AKT and AMPK signaling as a novel mechanism to induce sorafenib primary resistance in HCC.