Drivers In Non-small Cell Lung Cancer Research Articles

PEAC: An Ultrasensitive and Cost-Effective MRD Detection System in Non-small Cell Lung Cancer Using Plasma Specimen.

Circulating tumor DNA (ctDNA), a tumor-derived fraction of cell-free DNA (cfDNA), has emerged as a promising marker in targeted therapy, immunotherapy, and minimal residual disease (MRD) monitoring in postsurgical patients. However, ctDNA level in early-stage cancers and postsurgical patients is very low, which posed many technical challenges to improve the detection rate and sensitivity, especially in the clinical practice of MRD detection. These challenges usually include insufficient DNA input amount, limit of detection (LOD), and high experimental costs. To resolve these challenges, we developed an ultrasensitive ctDNA MRD detection system in this study, namely PErsonalized Analysis of Cancer (PEAC), to simultaneously detect up to 37 mutations, which account for 70–80% non-small cell lung cancer (NSCLC) driver mutations from low plasma sample volume and enables LOD of 0.01% at a single-site level. We demonstrated the high performance achieved by PEAC on both cfDNA reference standards and clinical plasma samples from three NSCLC patient cohorts. For cfDNA reference standards, PEAC achieved a specificity of 99% and a sensitivity of 87% for the mutations at 0.01% allele fraction. In the second cohort, PEAC showed 100% concordance rate between ddPCR and Next-generation sequencing (NGS) among 29 samples. In the third cohort, 22 of 59 patients received EGFR TKI treatment. Among them, three in four patients identified low level actionable gene mutations only by PEAC had partial responses after targeted therapy, demonstrating high ctDNA detection ability of PEAC. Overall, the developed PEAC system can detect the majority of NSCLC driver mutations using 8–10 ml plasma samples, and has the advantages of high detection sensitivity and lower costs compared with the existing technologies such as ddPCR and NGS. These advantages make the PEAC system quite appropriate for ctDNA and MRD detection in early-stage NSCLC and postsurgical recurrence monitoring.

Comprehensive Characterization of the Genomic Landscape in Chinese Pulmonary Neuroendocrine Tumors Reveals Prognostic and Therapeutic Markers (CSWOG-1901).

BackgroundPulmonary neuroendocrine tumors (pNETs) include typical carcinoid (TC), atypical carcinoid (AC), large cell neuroendocrine carcinoma (LCNEC), and small cell lung carcinoma (SCLC). The optimal treatment strategy for each subtype remains elusive, partly due to the lack of comprehensive understanding of their molecular features. We aimed to explore differential genomic signatures in pNET subtypes and identify potential prognostic and therapeutic biomarkers.MethodsWe investigated genomic profiles of 57 LCNECs, 49 SCLCs, 18 TCs, and 24 ACs by sequencing tumor tissues with a 520-gene panel and explored the associations between genomic features and prognosis.ResultsBoth LCNEC and SCLC displayed higher mutation rates for TP53, PRKDC, SPTA1, NOTCH1, NOTCH2, and PTPRD than TC and AC. Small cell lung carcinoma harbored more frequent co-alterations in TP53-RB1, alterations in PIK3CA and SOX2, and mutations in HIF-1, VEGF and Notch pathways. Large cell neuroendocrine carcinoma (12.7 mutations/Mb) and SCLC (11.9 mutations/Mb) showed higher tumor mutational burdens than TC (2.4 mutations/Mb) and AC (7.1 mutations/Mb). 26.3% of LCNECs and 20.8% of ACs harbored alterations in classical non-small cell lung cancer driver genes. The presence of alterations in the homologous recombination pathway predicted longer progression-free survival in advanced LCNEC patients with systemic therapy (P = .005) and longer overall survival (OS) in SCLC patients with resection (P = .011). The presence of alterations in VEGF (P = .048) and estrogen (P = .018) signaling pathways both correlated with better OS in patients with resected SCLC.ConclusionWe performed a comprehensive genomic investigation on 4 pNET subtypes in the Chinese population. Our data revealed distinctive genomic signatures in subtypes and provided new insights into the prognostic and therapeutic stratification of pNETs.

Targeting Oncogenic KRAS in Non-Small-Cell Lung Cancer.

Simple Summaryv-Ki-ras2 Kirsten rat sarcoma viral oncogene (KRAS) is the most common driver in NSCLC, and targeting oncogenic KRAS is a major challenge in the treatment of non-small-cell lung cancer (NSCLC). While several covalent KRAS G12C inhibitors have emerged as a novel anti-KRAS therapy, the development of combined therapies involving the targeting of oncogenic KRAS plus other targeted drugs is still required given the vast heterogeneity of KRAS-mutated tumors. In this review, we summarize the biological and immunological characteristics of oncogenic KRAS-driven NSCLC and the preclinical and clinical evidence for mutant KRAS-targeted therapies. We also discuss the mechanisms of resistance to KRAS G12C inhibitors and possible therapeutic strategies to overcome this drug resistance.Recent advances in molecular biology and the resultant identification of driver oncogenes have achieved major progress in precision medicine for non-small-cell lung cancer (NSCLC). v-Ki-ras2 Kirsten rat sarcoma viral oncogene (KRAS) is the most common driver in NSCLC, and targeting KRAS is considerably important. The recent discovery of covalent KRAS G12C inhibitors offers hope for improving the prognosis of NSCLC patients, but the development of combination therapies corresponding to tumor characteristics is still required given the vast heterogeneity of KRAS-mutated NSCLC. In this review, we summarize the current understanding of KRAS mutations regarding the involvement of malignant transformation and describe the preclinical and clinical evidence for targeting KRAS-mutated NSCLC. We also discuss the mechanisms of resistance to KRAS G12C inhibitors and possible combination treatment strategies to overcome this drug resistance.

Clinical validation of Guardant360 CDx as a blood-based companion diagnostic for sotorasib

ObjectivesEffective therapy for non–small-cell lung cancer (NSCLC) depends on morphological and genomic classification, with comprehensive screening for guideline-recommended biomarkers critical to guide treatment. Companion diagnostics, which provide robust genotyping results, represent an important component of personalized oncology. We evaluated the clinical validity of Guardant360 CDx as a companion diagnostic for sotorasib for detection of KRAS p.G12C, an important oncogenic NSCLC driver mutation. Materials and MethodsKRAS p.G12C was tested in NSCLC patients from CodeBreaK100 (NCT03600833) in pretreatment plasma samples using Guardant360 CDx liquid biopsy and archival tissue samples using therascreen® KRAS RGQ polymerase chain reaction (PCR) kit tissue testing. Matched tissue and plasma samples were procured from other clinical trials or commercial vendors, and results were compared. Demographics and clinical characteristics and objective response rate (ORR) were evaluated. ResultsOf 126 CodeBreaK patients, 112 (88.9%) were tested for KRASp.G12C mutations with Guardant360 CDx. Among 189 patients in the extended analysis cohort, the positive and negative percent agreement (95% CI) for Guardant360 CDx plasma testing relative to therascreen® KRAS RGQ PCR kit tissue testing were 0.71 (0.62, 0.79) and 1.00 (0.95, 1.00), respectively; overall percent agreement (95% CI) was 0.82 (0.76, 0.87). TP53 co-mutations were the most common regardless of KRAS p.G12C status (KRAS p.G12C–positive, 53.4%; KRAS p.G12C–negative, 45.5%). STK11 was co-mutated in 26.1% of KRAS p.G12C–positive samples. The ORR was similar among patients selected by plasma and tissue testing. ConclusionComprehensive genotyping for all therapeutic targets including KRAS p.G12C is critical for management of NSCLC. Liquid biopsy using Guardant360 CDx has clinical validity for identification of patients with KRASp.G12C–mutant NSCLC and, augmented by tissue testing methodologies as outlined on the approved product label, will identify patients for treatment with sotorasib.

SY28-4 Clinical development of RET inhibitors for RET fusion positive non-small cell lung cancer (NSCLC)

RET gene rearrangements retaining the kinase domain are oncogenic drivers in NSCLC, papillary thyroid cancer, and multiple other cancers. In NSCLC, the most common RET fusion partners are KIF5B (most common) and CCDC6. The frequency of RET fusion positive NSCLC was reported 1-2% and, it was also 2% (182/8621, between Feb. 2013 and Oct. 2020) in the East Asian lung cancer genomic screening (LC-SCRUM-Asia). Base on the LC-SCRUM-Asia clinical genomic database, the patient characteristics were median age 61 (29-85) years, female 62%, never smoker 64% and adenocarcinoma 97%. Because RET fusion is thus an attractive therapeutic target in NSCLC, multikinase inhibitors with RET inhibitor activity, such as vandetanib and cabozantinib, have been evaluated in prospective clinical trials. A clinical study of vandetanib for RET fusion positive NSCLC (LURET study) was conducted in Japan and objective response rate (ORR) was 53% and median progression free survival was 4.7 months. However, as a result of the nonselective nature of these multikinase inhibitors, patients had off-target adverse effects, such as hypertension, rash, and diarrhea and this resulted in only limited clinical efficacy. In contrast, the recent discovery and clinical validation of highly potent selective RET inhibitors such as selpercatinib (LOXO-292) and pralsetinib (BLU-667) demonstrated improved efficacy and a more favorable toxicity profile. These drugs appear to have broad activity across tumors with activating RET alterations. In a phase I/II clinical trial of selpercatinib (LIBRETTO-001), ORR 64% in 105 previously treated RET fusion positive NSCLC and 85% in 39 previously untreated patients were observed. RET-selective inhibitors selpercatinib and pralsetinib demonstrated favorable antitumor activity and safety profiles in RET fusion positive advanced NSCLC, and both received approval by the US FDA for it. In addition, the mechanisms of resistance to selective RET inhibitors are currently investigated.

ROS1 Targeted Therapies: Current Status.

Molecular drivers are increasingly identified as therapeutic targets for non-small cell lung cancer (NSCLC). This review focuses on the role of ROS1 inhibitors in treating relapsed/metastatic ROS-1 altered (ROS1+) NSCLC. Four FDA-approved drugs have significant activity against ROS1+ NSCLC: crizotinib, ciritinib, lorlatinib, and entrectinib. Each drug yields an overall response rates exceeding 60% with ciritinib, lorlatinib, and entrectinib possessing intracranial activity. The drugs have manageable toxicity profiles. ROS1 alterations are rare molecular drivers of NSCLC that can be effectively treated with a variety of ROS1-targetd drugs. New agents are being identified that may treat resistance mutations.

Driver Gene Mutations and Risk of Lymph Node Metastasis in Non-Small Cell Lung Cancer

Non-Small Cell Lung Cancer (NSCLC) lymph node status is closely related to its diagnosis, treatment, and prognosis. The lymph node status is an important basis for formulating clinical treatment strategies of NSCLC, therefore comprehensive and profound understanding of risk factors for lymph node metastasis is essential. There are many known factors for lymph node metastasis in NSCLC, such as pathological subtypes, tumor size, tumor location. Meanwhile, whether the mutation of the driver gene affects the lymph node metastasis is still lacking enough research. This article aims to elaborate the relationship between NSCLC driver gene mutation and lymph node metastasis, from NSCLC lymph node metastasis-related risk factors, driver genes and lymph node metastasis, metastatic lymph node mutation status analysis and detection these several aspects to summarize the latest research progress in NSCLC driver gene mutation and lymph node metastasis risk. It also fully explained the correlation between driver gene mutations and NSCLC tumor biological behaviors such as lymph node metastasis.

Clinical characteristics, co-mutations and outcomes of advanced non-small cell lung cancer (NSCLC) patients with KRAS mutations.

e21174 Background: Mutations (mt) in the KRAS gene are common oncogenic drivers in advanced NSCLC. The KRAS mt subtypes and certain co-mutations (co-mt) have prognostic and predictive implications. New drugs promise to uniquely target KRAS G12C, raising interest in studying the unique clinical and molecular characteristics of this subtype. Methods: We retrospectively identified 56 KRAS mt advanced NSCLC patients (pts) that underwent Next-Generation Sequencing (NGS) from 06/2015 to 12/2020. We used a commercial NGS panel that tested for > 300 genomic alterations, including substitutions, insertions, deletions and copy number alterations. For statistical analysis, we divided the patients into G12C and non-G12C groups. Results: In our cohort of 56 KRAS mt pts, median age was 67 (range: 58-74) with a predominance of females (63%) and heavy smokers (89%). KRAS G12C was the most common subtype 38%; G12V 14%, G12D 11%, G12S 11%, G13D 7% and others < 5% each. G12C, G12D and G13D groups had a higher proportion of PD-L1+ tumors (84%, 100%, and 100% respectively, p = 0.02) compared to other KRAS subtypes. Pts in G12C group were on average older (median age 71 vs 61, p = 0.02) than non-G12C. Most frequent co-mt in G12C were TP53 (33%), STK11 (29%), TET2 (19%), RB1 (14%), CDKN2A/B (14%) , MCL1 (14%) and ASXL1 (14%) ; for non-G12C, they were TP53 (54%), CDKN2A/B (37%), STK11 (34%) and RBM10 (17%). CDKN2A/B co-mt (37% vs 14%, p = 0.08) was significantly more frequent in non-G12C group and TET2 in G12C (19% vs 0%, p = 0.016). Non-G12C group more frequently had high TMB (17% vs 0%, p = 0.07) compared to G12C. No difference in survival was seen between G12C and non-G12C groups. We observed no difference in PFS (p = 0.31) or OS (p = 0.64) between smokers and no/light-smokers with KRAS mt. Co-mt with KEAP1 and SMARCA4 were significantly associated with survival in KRAS mt. Compared to KRAS+/KEAP1wt, KRAS +/ KEAP1+ pts had poor PFS (median 1.1 vs 7.5 m, p < 0.0001) and OS (1.1 vs. 27.8 m, p < 0.0001) measured from start of initial therapy. KRAS+/SMARCA4+ had worse PFS (1.0 vs 6.9 m, p < 0.0001) and OS (1.4 vs. 27.8, p = 0.0001) compared to KRAS+/SMARCA4wt. KRAS mt pts with STK11/KEAP1 that were treated with immunotherapy-based regimens had shorter PFS (1.1 vs 7.6 m, p = 0.001) and OS (1.4 vs 90.9 m, p = 0.0007) compared to those treated with chemotherapy alone. Conclusions: Our data shows that pts with KRAS co-mt with STK11/KEAP1 had worse PFS and OS with the addition of immunotherapy compared to chemotherapy alone, highlighting the potential implications of these co-mt patterns on treatment outcomes. The types of co-mts are similar between KRAS G12C and non-G12C, with the exception of CDKN2A/B (less likely) and TET2 (more likely). Larger data sets are warranted to confirm our observations and determine if these co-mts may create a predictive model for individualized therapy for KRAS mt pts, potentially independent of current predictive markers.

Unique Profile of Driver Gene Mutations in Patients With Non-Small-Cell Lung Cancer in Qujing City, Yunnan Province, Southwest China.

ObjectiveQujing City, Yunnan Province, China, has a high incidence of lung cancer and related mortality. The etiology of NSCLC in Qujing area and distribution of associated molecular aberrations has not been fully elucidated. This study aimed to reveal the profile of driver gene mutations in patients with non-small-cell lung cancer (NSCLC) in Qujing and explore their relationships with clinicopathological characteristics.MethodsIn this study, the mutation profiles of NSCLC driver genes, including EGFR, ALK, ROS1, KRAS, BRAF, RET, MET, HER2, NRAS, and PIK3CA, were investigated in patients with NSCLC from Qujing and compared with those from other regions in Yunnan Province. The associations between molecular mutations and clinicopathological characteristics were further analyzed.ResultsA distinct profile of driver gene mutations was discovered in patients with NSCLC from Qujing. Interestingly, a higher proportion of EGFR compound mutations, including G719X + S768I (19.65% vs 3.38%, P < 0.0001) and G719X + L861Q (21.10% vs 2.82%, P < 0.0001), was observed in patients with NSCLC in Qujing compared with patients in non-Qujing area, besides significantly different distributions of EGFR (46.01% vs. 51.07%, P = 0.0125), ALK (3.17% vs. 6.97%, P = 0.0012), ROS1 (0.5% vs. 2.02%, P = 0.0113), and KRAS (23.02% vs. 7.85%, P < 0.0001). Further, EGFR compound mutations were more likely associated with the occupation of patients (living/working in rural areas, e.g., farmers). Moreover, KRAS G12C was the dominant subtype (51.11% vs 25.00%, P = 0.0275) among patients with NSCLC having KRAS mutations in Qujing.ConclusionsPatients with NSCLC in Qujing displayed a unique profile of driver gene mutations, especially a higher prevalence of EGFR compound mutations and dominant KRAS G12C subtype, in this study, indicating a peculiar etiology of NSCLC in Qujing. Therefore, a different paradigm of therapeutic strategy might need to be considered for patients with NSCLC in Qujing.

Pralsetinib for the treatment of non-small cell lung cancer.

The identification of oncogenic drivers and the subsequent development of targeted therapies have been established as biomarker-based care for metastatic non-small cell lung cancer (NSCLC) patients. Rearranged during transfection (RET) events have been reported to be oncogenic drivers in NSCLC and were more common in patients who i) were young; ii) had adenocarcinoma histology; and iii) had never smoked. Phase II studies indicated the limited efficacy of multi-targeted tyrosine kinase inhibitors in patients with NSCLC that have a confirmed RET event. Consequently, there has been ongoing research to develop more potent and specific RET tyrosine kinase inhibitors. Recently, a novel and specific RET inhibitor, pralsetinib (BLU-667), has been reported to have excellent efficacy and low off-target toxicity in RET cancer patients. In this review, we summarize the clinical data regarding the use of pralsetinib in NSCLC patients.

Driver genes expression and clinical characteristics of targeted therapy in non-small cell lung cancer in Yunnan-Kweichow Plateau

Objective: To analyze the expressions of non-small-cell lung cancer (NSCLC) driver genes and their mutation distribution characteristics in the Yunnan-Kweichow plateau, and to provide evidences for personalized molecular targeted therapy of lung cancer in high-incidence areas. Methods: A retrospective analysis was performed on the medical records of patients with NSCLC who underwent combined lung cancer 8 gene detection, including epidermal growth factor receptor (EGFR), rat sarcoma viral oncogene (RAS), anaplastic lymphoma kinase (ALK), RET proto-oncogene (RET), v-Raf murine sarcoma viral oncogene homolog (BRAF), ROS proto-oncogene 1 (ROS1), human epidermal growth factor receptor-2 (HER-2), and cellular-mesenchymal to epithelial transition factor (MET), from January 2016 to August 2019 in Yunnan Cancer Hospital. Besides, we analyzed the expressions of NSCLC driver genes and their mutation distributions. Results: The positive rate of NSCLC driver genes in Yunnan was 67.05%(1 508/2 249). The mutation rates in Xishuangbanna (76.92%), Yuxi (72.38%), Xuanwei (71.88%), Qujing (71.24%), and Honghe (71.79%) were significantly higher than other areas. The mutation rates of Hui (84.38%), Hani (85.00%), Zhuang (75.00%), Buyi (100%), Manchu (100%), Tujia (100%) and Achang (100%) are significantly higher than the minority national average. Driver gene mutations were related to gender (P<0.001), smoking history (P<0.001), age (P<0.001), pathological type (P<0.001), and whether the Xuanwei area (P=0.027), but not related to the nationality (P=0.748) and family history of lung cancer (P=0.676). The mutation rates of EGFR, RAS, BRAF, HER-2 and MET genes were 44.46%, 10.98%, 1.24%, 0.89% and 0.76%, and the rearrangement rates of ALK, RET and ROS1 genes were 4.67%, 1.29% and 0.89%, respectively.The mutation rate of EGFR in females was 56.67%, which was higher than 33.19% in males (P<0.001). The mutation rate of RAS in males was 12.66%, which was higher than 9.17% in females (P=0.010). The mutation rate of RAS in the Han was 11.49%, which was higher than 7.17% in the minority (P=0.032). The rate of RAS mutation in Xuanwei patients was 24.74%, significantly higher than 8.15% in non-Xuanwei area (P<0.001), and the EGFR mutation rate was 40.63%, which was lower than 45.25% in non-Xuanwei area (P=0.045). The rate of ALK rearrangement in Xuanwei patients was 1.56%, which was significantly lower than 5.31% in the non-Xuanwei area (P<0.001), and no HER-2 mutation patients were detected in Xuanwei area. The mutation rate of EGFR in patients with non-smoking history was 51.10%, significantly higher than 29.70% of patients with smoking history (P<0.001). Meanwhile, the rate of ALK rearrangement with non-smoking history patients was 5.35%, which was also higher than 3.16% of patients with smoking history (P<0.001). The rate of RAS mutation in patients with non-smoking history was 9.34%, lower than 14.63% of patients with smoking history (P=0.008). Conclusions: The positive rate of driven gene expression in NSCLC patients from the Yunnan-Kweichow Plateau is slightly lower than the national average. The rates of EGFR and RAS mutations are similar to the domestic average. The rates of ROS1, ALK and RET genes rearrangements and the rates of BRAF, HER2 and MET gene mutations are slightly lower than the national average. EGFR, RAS and ALK genes in the NSCLC patients from Yunnan-Kweichow Plateau have high positive rates, and display different demographic and clinical characteristics, which are of great significance in the selection of targeted therapy populations.

NT5DC2 suppression restrains progression towards metastasis of non-small-cell lung cancer through regulation p53 signaling

Non-small cell lung cancer (NSCLC) is a leading cause of tumor mortality worldwide. Nevertheless, the molecular mechanisms revealing NSCLC progression are still unclear. 5′-Nucleotidase domain containing 2 (NT5DC2), as a member of the NT5DC family, contains a haloacid dehalogenase motif localized in the N-terminus of these proteins. NT5DC2 plays an essential role in cancer development. The purpose of the study was to explore NT5DC2’s role in tumorigenesis and its potential mechanisms in NSCLC. Our findings showed that NT5DC2 expression was significantly up-regulated in clinical NSCLC tissues compared to the paired non-tumor tissues. Functionally, NT5DC2 knockdown in A549 and H1299 cells markedly reduced cell proliferation, migration and invasion. On the contrary, NT5DC2 over-expression promoted NSCLC cell proliferative, migrative and invasive capacities. Additionally, NT5DC2 down-regulation significantly induced the G2 cell cycle arrest and apoptosis in NSCLC cells. Mechanistically, p53 might be a target of NT5DC2. The expression of p53 was highly induced in NSCLC cells with NT5DC2 knockdown, and opposite result was detected when NT5DC2 was over-expressed. Importantly, we found that NT5DC2 knockdown-restrained cell proliferation and -induced apoptosis was almost abrogated by p53 down-regulation in NSCLC cells, demonstrating that NT5DC2-regulated cell proliferation and apoptotic cell death in NSCLC was p53-dependent. Finally, we confirmed that reducing NT5DC2 could inhibit NSCLC tumorigenesis and hepatic metastasis in vivo. Collectively, these results suggested that NT5DC2 may be a potential driver of NSCLC, providing a new therapeutic target for the clinical treatment of NSCLC.

Non-amplification genetic alterations of HER2 gene in non-small cell lung carcinoma

AimsThe present study investigated the incidence and spectrum of human epidermal growth factor receptor 2 (HER2) mutations, associated clinicopathological characteristics and the co-occurrence of HER2 gene amplification in the HER2...

Checkpoint Blockade in Lung Cancer With Driver Mutation: Choose the Road Wisely.

Immune checkpoint blockade with PD-(L)1 antibodies has revolutionized the treatment of advanced non-small cell lung cancer (NSCLC). Similarly, the identification and targeting of oncogene drivers in metastatic NSCLC has dramatically improved patient outcomes with an expanding list of potentially actionable alterations and targeted therapies. Many of these molecular aberrations are more common in patients with little or no smoking history and adenocarcinoma histology. Certain molecular subsets of NSCLC, though gaining greatly from targeted therapy approaches, may derive less benefit from immune checkpoint blockade. The optimal identification, targeting, and sequencing of targeted therapies, immunotherapy, and chemotherapy are essential to continue to improve patient outcomes in advanced NSCLC. Herein, we review the role of immunotherapy in locally advanced and metastatic disease for patients with actionable driver alterations. Never-smoking patients have a high probability of having lung cancer that harbors one of these molecular aberrations that can be matched to a tyrosine kinase inhibitor with greatly improved clinical outcomes. Some of these patients with driver mutations may derive less benefit from immune checkpoint inhibitor approaches (either alone or combined with chemotherapy), especially compared with smoking-associated NSCLC. Given that PD-1 blockade alone or with platinum-based chemotherapy is the de facto first-line therapy (depending on level of PD-L1 expression) for nontargetable metastatic NSCLC, we also review treatment in never-smoking patients for whom molecular testing results are pending and the likelihood of identifying a driver mutation is high.

New Targets in Lung Cancer (Excluding EGFR, ALK, ROS1).

Over the last two decades, the identification of targetable oncogene drivers has revolutionized the therapeutic landscape of non-small cell lung cancer (NSCLC). The extraordinary progresses made in molecular biology prompted the identification of several rare molecularly defined subgroups. In this review, we will focus on the novel and emerging actionable oncogenic drivers in NSCLC. Recently, novel oncogene drivers emerged as promising therapeutic targets besides the well-established EGFR mutations, and ALK/ROS1 rearrangements, considerably expanding the list of potential exploitable genetic aberrations. However, the therapeutic algorithm in these patients is far less defined. The identification of uncommon oncogene drivers is reshaping the diagnostic and therapeutic approach to NSCLC. The introduction of novel highly selective inhibitors is expanding the use of targeted therapies to rare and ultra-rare subsets of patients, further increasing the therapeutic armamentarium of advanced NSCLC.

Brain Metastases in Lung Cancers with Emerging Targetable Fusion Drivers.

The management of non-small cell lung cancer (NSCLC) has transformed with the discovery of therapeutically tractable oncogenic drivers. In addition to activating driver mutations, gene fusions or rearrangements form a unique sub-class, with anaplastic lymphoma kinase (ALK) and c-ros oncogene 1 (ROS1) targeted agents approved as the standard of care in the first-line setting for advanced disease. There are a number of emerging fusion drivers, however, including neurotrophin kinase (NTRK), rearrangement during transfection (RET), and neuregulin 1 (NRG1) for which there are evolving high-impact systemic treatment options. Brain metastases are highly prevalent in NSCLC patients, with molecularly selected populations such as epidermal growth factor receptor (EGFR) mutant and ALK-rearranged tumors particularly brain tropic. Accordingly, there exists a substantial body of research pertaining to the understanding of brain metastases in such populations. Little is known, however, on the molecular mechanisms of brain metastases in those with other targetable fusion drivers in NSCLC. This review encompasses key areas including the biological underpinnings of brain metastases in fusion-driven lung cancers, the intracranial efficacy of novel systemic therapies, and future directions required to optimize the control and prevention of brain metastases.

RBBP6 induces non-small cell lung cancer cell proliferation and high expression is associated with poor prognosis.

Lung cancer is the most common cause of cancer-associated mortality in China with 85% of patients having non-small cell lung cancer (NSCLC). Identifying NSCLC driver genes and prognostic markers is critical to reducing these numbers. The studies of retinoblastoma binding protein 6 (RBBP6) performed on NSCLC is limited. The present study aimed to investigate the molecular function and the prognostic potential of RBBP6 in NSCLC using the A549 cell line and patient samples, respectively. The functional effect on cancer cell proliferation and prognostic value of RBBP6 were examined in vitro and in vivo using reverse transcription-quantitative PCR, immunofluorescence, immunohistochemistry (IHC) and xenograft implantation. The results demonstrated that RBBP6 mRNA expression was significantly higher in NSCLC tissues compared with in adjacent normal samples. When RBBP6 mRNA expression was interfered with using short hairpin RNA, A549 cell proliferation and xenograft tumor growth were reduced. Additionally, IHC and survival analysis demonstrated that patients with NSCLC with high expression levels of RBBP6 had a shorter median overall survival time compared with patients with low RBBP6 expression (31 vs. 51.5 months), and this was more prominent in stage I–II patients (43 vs. >67 months). High expression levels of RBBP6 indicated poor prognosis in patients with NSCLC. This may be due to the ability of RBBP6 to promote cancer cell proliferation. RBBP6 may be a potential prognostic biomarker and a therapeutic target for NSCLC.

Cancer progression is mediated by proline catabolism in non-small cell lung cancer.

Dysregulated metabolism contributes to cancer initiation and progression, but the key drivers of these pathways are just being discovered. Here, we report a critical role for proline catabolism in non-small cell lung cancer (NSCLC). Proline dehydrogenase (PRODH) is activated to reduce proline levels by the chromatin remodeling factor lymphoid-specific helicase (LSH), an epigenetic driver of NSCLC. PRODH promotes NSCLC tumorigenesis by inducing epithelial to mesenchymal transition (EMT) and IKKα-dependent inflammatory genes, including CXCL1, LCN2, and IL17C. Consistently, proline addition promotes the expression of these inflammatory genes, as well as EMT, tumor cell proliferation, and migration in vitro and tumor growth in vivo, while the depletion or inhibition of PRODH blocks these phenotypes. In summary, we reveal an essential metabolic pathway amenable to targeting in NSCLC.

Current management of RET rearranged non-small cell lung cancer.

The identification of oncogenic drivers, and the subsequent development of targeted therapies established biomarker-based care for metastatic non-small cell lung cancer (NSCLC). Biomarker testing is standard of care in NSCLC patients with adenocarcinoma because multiple targeted therapies are available. Rearranged during transfection (RET) rearrangements were identified as oncogenic drivers in NSCLC, and are more common among younger patients, adenocarcinoma histology, and patients with a history of never smoking. The prevalence is estimated to be 1–2% among patients with adenocarcinoma histology. The most common rearrangement is between intron 11 of the RET gene and intron 15 of the KIF5B gene, and the next most frequent rearrangement is with the CCDC6 gene. RET rearrangements lead to constitutive activation of the RET tyrosine kinase and increased cell proliferation, migration, and survival. Phase II studies investigated the activity of multi-targeted tyrosine kinase inhibitors in patients with NSCLC with a confirmed RET rearrangement. These agents have limited potency against RET, and activity against the epidermal growth factor receptor and vascular endothelial growth factor pathways. These agents revealed modest activity, and were poorly tolerated due to the off-target toxicities. These struggles contributed to the development of more potent and specific RET tyrosine kinase inhibitors. Preliminary results from early phase trials of selpercatinib (LOXO-292) and pralsetinib (BLU-667) revealed promising efficacy and improved tolerability. The availability of these agents will make routine testing for RET rearrangements a priority.

Recent Progress in Rare Oncogenic Drivers and Targeted Therapy For Non-Small Cell Lung Cancer.

Non-small cell lung cancer (NSCLC) is frequently associated with oncogenic driver mutations, which play an important role in carcinogenesis and cancer progression. Targeting epidermal growth factor receptor (EGFR) mutations and anaplastic lymphoma kinase rearrangements has become standard therapy for patients with these aberrations because of the greater improvement of survival, tolerance, and quality-of-life compared to chemotherapy. Clinical trials for emerging therapies that target other less common driver genes are generating mixed results. Here, we review the literature on rare drivers in NSCLC with frequencies lower than 5% (e.g., ROS1, RET, MET, BRAF, NTRK, HER2, NRG1, FGFR1, PIK3CA, DDR2, and EGFR exon 20 insertions). In summary, targeting rare oncogenic drivers in NSCLC has achieved some success. With the development of new inhibitors that target these rare drivers, the spectrum of targeted therapy has been expanded, although acquired resistance is still an unavoidable problem.