In non-small cell lung cancer (NSCLC), the most frequent oncogenic mutation in western countries is KRAS, for which, however, there remains no clinically approved targeted therapies. Recent progress on high biological heterogeneity including diverse KRAS point mutations, varying dependence on mutant KRAS, wide spectrum of other co-occurring genetic alterations, as well as distinct cellular status across the epithelial-to-mesenchymal transition (EMT), has not only deepened our understanding about the pathobiology of KRAS-mutant NSCLC but also brought about unprecedented new hopes for precision treatment of patients. In this review, we provide an update on the most recent advances in KRAS-mutant lung cancer, with a focus on mechanistic insights into tumor heterogeneity, the potential clinic implications and new therapies on horizons tailored for KRAS-mutant lung cancer.

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We provide the first evidence for ER stress and the adaptive UPR signalling in chemotherapy resistance of MPM, which suggests that perturbation of the UPR by altering ER stress is a novel strategy to treat chemotherapy-refractory MPM.

The prognosis of patients after bilateral surgical treatment with curative intent for BMPLC was shown to be promising. The use of a limited resection procedure for the contralateral second nodule in cases with stage I BMPLC did not have a negative effect on the 5-year overall survival. Postoperative pathologic diagnosis classified by the most advanced TNM had a good correlation with prognosis in patients with BMPLC.

The data presented in the current study support using PCI in patients with p-stage II/III disease but not in patients with p-stage I disease. A relatively lower risk for brain metastases in p-stage I patients might explain the inferior efficacy of PCI in this population.

Drug resistance and tumor heterogeneity are formidable challenges in cancer medicine, which is particularly relevant for KRAS -mutant cancers, the epitome of malignant tumors recalcitrant to targeted therapy efforts and first-line chemotherapy. In this study, we delineate that KRAS -mutant lung cancer cells resistant to pemetrexed (MTA) and anti-MEK drug trametinib acquire an exquisite dependency on endoplasmic reticulum (ER) stress signaling, rendering resistant cancer cells selectively susceptible to blockage of HSP90, the receptor tyrosine kinase AXL, the eukaryotic translation initiation factor 4E (eIF4E), and the unfolded protein response (UPR). Mechanistically, acquisition of drug resistance enables KRAS -mutant lung cancer cells to bypass canonical KRAS effectors but entail hyperactive AXL/eIF4E, increased protein turnover in the ER, and adaptive activation of an ER stress-relief UPR survival pathway whose integrity is maintained by HSP90. Notably, the unique dependency and sensitivity induced by drug resistance are applicable to KRAS -mutant lung cancer cells undergoing de novo intratumor heterogeneity. In line with these findings, HSP90 inhibitors synergistically enhance antitumor effects of MTA and trametinib, validating a rational combination strategy to treat KRAS -mutant lung cancer. Collectively, these results uncover collateral vulnerabilities co-occurring with drug resistance and tumor heterogeneity, informing novel therapeutic avenues for KRAS -mutant lung cancer.

Background: Surgical treatment is thought to be the most effective strategy for multiple small nodules.However, in general, one-stage bilateral resection is not recommended due to its highly invasive nature.Methods: Clinical records of patients undergoing one-stage bilateral resections of multiple pulmonary nodules between January 2009 and September 2014 in a single institution were retrospectively reviewed.Results: Simultaneous bilateral pulmonary resection by conventional video-assisted thoracic surgery (VATS) was undertaken in 29 patients. Ground glass opacity (GGO) accounted for 71.9% (46/64) of total lesions, including 26 pure GGO and 20 mixed GGO lesions. One case underwent bilateral lobectomy that was complicated by postoperative dyspnea. Lobar-sublobar (L/SL) resection and bilateral sublobar resection (SL-SL) were conducted in 16 and 12 cases, respectively, and most of these cases had uneventful postoperative courses.There was no significant difference with regard to postoperative complications (P=0.703), duration of use of chest drains (P=0.485), between one-and two-stage groups. Mean postoperative follow-up in cases of primary lung cancer was 31.4 (range, 10-51) months. There was neither recurrence nor deaths at final follow-up. Conclusions Materials and methods PatientsThe study was approved by the ethics committee of Shanghai Chest Hospital. During the period of Jan 1 2009 to Sep 30 2014, cases performed with various pulmonary resections at our department were retrospectively reviewed. Twenty nine cases underwent single-stage bilateral operations of multiple pulmonary nodules were identified. For comparison, 89 patients with bilateral multiple nodules who underwent two-stage operations at the same period were also reviewed. Clinical and histologic features and surgical outcomes were studied. Surgical procedureGeneral anesthesia with double-lumen endotracheal intubation was administered.Single-stage bilateral surgical treatment by video-assisted thoracic surgery (VATS) was applied based on the following rules: patients with good performance status, patient's informed consent, characteristics of multiple pulmonary foci and individual surgeon's experience. The choice of surgical types comprehensively depends on the site of tumors, the evaluation of cardiopulmonary function reserve and outcomes of intraoperative frozen sections. Single-stage resection was performed with starting on the side of the less invasive resection, such as segmentectomy and wedge resection, generally depending on the size and morphology on preoperative chest computed tomography (CT). For planed bilateral sublobar resections, the priority was given to the right side.The patient was placed in the lateral decubitus position. After a one-sided procedure, the patient was rotated to the opposite side for a second resection. Cushions were used to lift the patient to avoid kicking or compression to the contralateral chest tube during positioning. Multiple primary lung cancer was diagnosed based on Martini-Melamed criteria (3).The comp...

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