Fusion genes in pancreatic tumors.

Gene fusions and rearrangements play a crucial role in tumor biology. They are rare events typically detected in KRAS wild-type (WT) pancreatic tumors. Their identification can inform clinical management by enabling precision oncology, as fusions involving BRAF, FGFR2, RET, NTRK, NRG1, and ALK represent actionable targets in KRAS-WT cancers, and serve diagnostic purposes since fusions involving PRKACA/B represent the diagnostic hallmark of intraductal oncocytic papillary neoplasms (IOPNs). Although they are rare, the therapeutic and diagnostic importance of these genomic events should not be underestimated, highlighting the need for quality-ensured molecular diagnostics in the management of cancer. Herein we review the existing literature on the role of fusion genes in pancreatic tumors and their clinical potential as effective biomarkers and therapeutic targets.

Characterization of two transcriptomic subtypes of marker-null large cell carcinoma of the lung suggests different origin and potential new therapeutic perspectives.

Pulmonary large cell carcinoma (LCC) is an undifferentiated neoplasm lacking morphological, histochemical, and immunohistochemical features of small cell lung cancer, adenocarcinoma (ADC), or squamous cell carcinoma (SCC). The available molecular information on this rare disease is limited. This study aimed to provide an integrated molecular overview of 16 cases evaluating the mutational asset of 409 genes and the transcriptomic profiles of 20,815 genes. Our data showed that TP53 was the most frequently inactivated gene (15/16; 93.7%) followed by RB1 (5/16; 31.3%) and KEAP1 (4/16; 25%), while CRKL and MYB genes were each amplified in 4/16 (25%) cases and MYC in 3/16 (18.8%) cases; transcriptomic analysis identified two molecular subtypes including a Pure-LCC and an adenocarcinoma like-LCC (ADLike-LCC) characterized by different activated pathways and cell of origin. In the Pure-LCC group, POU2F3 and FOXI1 were distinctive overexpressed markers. A tuft cell-like profile and the enrichment of a replication stress signature, particularly involving ATR, was related to this profile. Differently, the ADLike-LCC were characterized by an alveolar-cell transcriptomic profile and association with AIM2 inflammasome complex signature. In conclusion, our study split the histological marker-null LCC into two different transcriptomic entities, with POU2F3, FOXI1, and AIM2 genes as differential expression markers that might be probed by immunohistochemistry for the differential diagnosis between Pure-LCC and ADLike-LCC. Finally, the identification of several signatures linked to replication stress in Pure-LCC and inflammasome complex in ADLike-LCC could be useful for designing new potential therapeutic approaches for these subtypes.

An Overview of Circulating Biomarkers in Neuroendocrine Neoplasms: A Clinical Guide.

Neuroendocrine neoplasms (NENs) are a heterogeneous group of diseases that are characterized by different behavior and clinical manifestations. The diagnosis and management of this group of tumors are challenging due to tumor complexity and lack of precise and widely validated biomarkers. Indeed, the current circulating mono-analyte biomarkers (such as chromogranin A) are ineffective in describing such complex tumors due to their poor sensitivity and specificity. In contrast, multi-analytical circulating biomarkers (including NETest) are emerging as more effective tools to determine the real-time profile of the disease, both in terms of accurate diagnosis and effective treatment. In this review, we will analyze the capabilities and limitations of different circulating biomarkers focusing on three relevant questions: (1) accurate and early diagnosis; (2) monitoring of disease progression and response to therapy; and (3) detection of early relapse.

Transcriptome analysis of primary sporadic neuroendocrine tumours of the intestine identified three different molecular subgroups.

BACKGROUND: Intestinal neuroendocrine tumours (I-NETs) represent a non-negligible entity among intestinal neoplasms, with metastatic spreading usually present at the time of diagnosis. In this context, effective molecular actionable targets are still lacking. Through transcriptome analysis, we aim at refining the molecular taxonomy of I-NETs, also providing insights towards the identification of new therapeutic vulnerabilities. MATERIALS AND METHODS: A retrospective series of 38 primary sporadic, surgically-resected I-NETs were assessed for transcriptome profiling of 20,815 genes. RESULTS: Transcriptome analysis detected 643 highly expressed genes. Unsupervised hierarchical clustering, differential expression analysis and gene set enriched analysis identified three different tumour clusters (CL): CL-A, CL-B, CL-C. CL-A showed the overexpression of ARGFX, BIRC8, NANOS2, and SSTR4 genes. Its most characterizing signatures were those related to cell-junctions, and activation of mTOR and WNT pathway. CL-A was also enriched in T CD8 + lymphocytes. CL-B showed the overexpression of PCSK1, QPCT, ST18, and TPH1 genes. Its most characterizing signatures were those related to adipogenesis, neuroendocrine metabolism, and splice site machinery-related processes. CL-B was also enriched in T CD4 + lymphocytes. CL-C showed the overexpression of ALB, ANG, ARG1, and HP genes. Its most characterizing signatures were complement/coagulation and xenobiotic metabolism. CL-C was also enriched in M1/2 macrophages. These CL-based differences may have therapeutic implications in refining the management of I-NET patients. At last, we described a specific gene-set for differentiating I-NET from pancreatic NET. DISCUSSION: Our data represent an additional step for refining the molecular taxonomy of I-NET, identifying novel transcriptome subgroups with different biology and therapeutic opportunities.

Clinical and Genomic Characterization of Pancreatic Ductal Adenocarcinoma with Signet-Ring/Poorly Cohesive Cells.

Signet-ring cell (SRC)/poorly cohesive cell carcinoma is an aggressive variant of pancreatic ductal adenocarcinoma (PDAC). This study aimed to clarify its clinicopathologic and molecular profiles based on a multi-institutional cohort of 20 cases. The molecular profiles were investigated using DNA and RNA sequencing. The clinicopathologic parameters and molecular alterations were analyzed based on survival indices and using a validation/comparative cohort of 480 conventional PDAC patients. The primary findings were as follows: (1) clinicopathologic features: SRC carcinomas are highly aggressive neoplasms with poor prognosis, and the lungs are elective metastatic sites; (2) survival analysis: a higher SRC component was indicative of poorer prognosis. In particular, the most clinically significant threshold of SRC was 80%, showing statistically significant differences in both disease-specific and disease-free survival; (3) genomic profiles: SRC carcinomas are similar to conventional PDAC with the most common alterations affecting the classic PDAC drivers KRAS (70% of cases), TP53 (55%), SMAD4 (25%), and CDKN2A (20%). EGFR alterations, RET::CCDC6 fusion gene, and microsatellite instability (3 different cases, 1 alteration per case) represent novel targets for precision oncology. The occurrence of SMAD4 mutations was associated with poorer prognosis; (4) pancreatic SRC carcinomas are genetically different from gastric SRC carcinomas: CDH1, the classic driver gene of gastric SRC carcinoma, is not altered in pancreatic SRC carcinoma; (5) transcriptome analysis: the cases clustered into 2 groups, one classical/exocrine-like, and the other squamous-like; and (6) SRC carcinoma-derived organoids can be successfully generated, and their cultures preserve the histologic and molecular features of parental SRC carcinoma. Although pancreatic SRC carcinoma shares similarities with conventional PDAC regarding the most important genetic drivers, it also exhibits important differences. A personalized approach for patients with this tumor type should consider the clinical relevance of histologic determination of the SRC component and the presence of potentially actionable molecular targets.

Extrahepatic Distal Cholangiocarcinoma vs. Pancreatic Ductal Adenocarcinoma: Histology and Molecular Profiling for Differential Diagnosis and Treatment.

Pancreatic ductal adenocarcinoma (PDAC) and distal cholangiocarcinoma (dCCA) are very aggressive tumors with a high mortality rate. Pancreas and distal bile ducts share a common embryonic development. Hence, PDAC and dCCA exhibit similar histological features that make a differential diagnosis during routine diagnostic practice challenging. However, there are also significant differences, with potential clinical implications. Even if PDAC and dCCA are generally associated with poor survival, patients with dCCA seem to present a better prognosis. Moreover, although precision oncology-based approaches are still limited in both entities, their most important targets are different and include alterations affecting BRCA1/2 and related genes in PDAC, as well as HER2 amplification in dCCA. Along this line, microsatellite instability represents a potential contact point in terms of tailored treatments, but its prevalence is very low in both tumor types. This review aims at defining the most important similarities and differences in terms of clinicopathological and molecular features between these two entities, also discussing the main theranostic implications derived from this challenging differential diagnosis.

An Insight on Functioning Pancreatic Neuroendocrine Neoplasms.

Pancreatic neuroendocrine neoplasms (PanNENs) are rare neoplasms arising from islets of the Langerhans in the pancreas. They can be divided into two groups, based on peptide hormone secretion, functioning and nonfunctioning PanNENs. The first group is characterized by different secreted peptides causing specific syndromes and is further classified into subgroups: insulinoma, gastrinoma, glucagonoma, somatostatinoma, VIPoma and tumors producing serotonin and adrenocorticotrophic hormone. Conversely, the second group does not release peptides and is usually associated with a worse prognosis. Today, although the efforts to improve the therapeutic approaches, surgery remains the only curative treatment for patients with PanNENs. The development of high-throughput techniques has increased the molecular knowledge of PanNENs, thereby allowing us to understand better the molecular biology and potential therapeutic vulnerabilities of PanNENs. Although enormous advancements in therapeutic and molecular aspects of PanNENs have been achieved, there is poor knowledge about each subgroup of functioning PanNENs.Therefore, we believe that combining high-throughput platforms with new diagnostic tools will allow for the efficient characterization of the main differences among the subgroups of functioning PanNENs. In this narrative review, we summarize the current landscape regarding diagnosis, molecular profiling and treatment, and we discuss the future perspectives of functioning PanNENs.

Combined Large Cell Neuroendocrine Carcinomas of the Lung: Integrative Molecular Analysis Identifies Subtypes with Potential Therapeutic Implications.

BACKGROUND: Combined large cell neuroendocrine carcinoma (CoLCNEC) is given by the association of LCNEC with adeno or squamous or any non-neuroendocrine carcinoma. Molecular bases of CoLCNEC pathogenesis are scant and no standardized therapies are defined. METHODS: 44 CoLCNECs: 26 with adenocarcinoma (CoADC), 7 with squamous cell carcinoma (CoSQC), 3 with small cell carcinoma (CoSCLC), 4 with atypical carcinoid (CoAC) and 4 napsin-A positive LCNEC (NapA+), were assessed for alterations in 409 genes and transcriptomic profiling of 20,815 genes. RESULTS: Genes altered included TP53 (n = 30), RB1 (n = 14) and KRAS (n = 13). Targetable alterations included six KRAS G12C mutations and ALK-EML4 fusion gene. Comparison of CoLCNEC transcriptomes with 86 lung cancers of pure histology (8 AC, 19 ADC, 19 LCNEC, 11 SCLC and 29 SQC) identified CoLCNEC as a separate entity of neuroendocrine tumours with three different molecular profiles, two of which showed a non-neuroendocrine lineage. Hypomethylation, activation of MAPK signalling and association to immunotherapy signature specifically characterized each of three CoLCNEC molecular clusters. Prognostic stratification was also provided. CONCLUSIONS: CoLCNECs are an independent histologic category. Our findings support the extension of routine evaluation of KRAS mutations, fusion genes and immune-related markers to offer new perspectives in the therapeutic management of CoLCNEC.

Genomic characterization of undifferentiated sarcomatoid carcinoma of the pancreas.

Undifferentiated sarcomatoid carcinoma (USC) of the pancreas is a rare but especially aggressive variant of pancreatic ductal adenocarcinoma (PDAC), composed of at least 80% of sarcomatoid cells. This study aimed to elucidate its clinicopathological and molecular features. The study cohort included 10 patients with pancreatic USC. Clinicopathological parameters were determined for each patient. The molecular profile was investigated using next-generation sequencing (NGS). Histologically, all tumors were hypercellular neoplasms with spindle-shaped or sarcomatoid cells. All patients showed vascular and perineural invasion. Most patients had a poor prognosis. NGS showed important similarities with conventional PDAC, including frequent alterations in the classic PDAC drivers, KRAS (100% of cases), TP53 (90%), and CDKN2A (60%). There were also some important distinctions from conventional PDAC: 1) SMAD4, a typical PDAC driver gene, was mutated in only one case (10%); 2) Another distinctive molecular feature was the recurrent KRAS amplification (30% of cases), which is very rare in conventional PDAC. It has been previously reported in another subtype of pancreatic undifferentiated carcinoma, the rhabdoid variant, and may be a key event leading to the acquisition of an undifferentiated phenotype in a subgroup of cases; 3) Lastly, in two different cases, we detected two potentially actionable targets, not belonging to the typical PDAC molecular landscape, such as MCL1 amplification and POLQ mutation. Our study sheds light on this rare tumor type, which shows aggressive biological behavior and few druggable alterations. The most distinctive molecular features of pancreatic USC are the paucity of SMAD4 alterations and recurrent KRAS amplification.

Undifferentiated Sarcomatoid Carcinoma of the Pancreas: From Histology and Molecular Pathology to Precision Oncology.

Undifferentiated sarcomatoid carcinoma of the pancreas (SCP) is a rare and aggressive subtype of pancreatic cancer. Histologically, SCP is a poorly differentiated tumor characterized by the lack of glandular differentiation and the presence of mesenchymal-like, spindle-shaped tumor cells. Due to its rarity, only sporadic cases have been reported, while its molecular characterization has not been sufficiently described. Surgical resection with curative intent is the gold-standard of SCP management, but this strategy is possible only in a small proportion of cases due to SCP early metastasization. Although SCP is generally associated with a poor prognosis, some clinical cases amenable to surgical resection and followed by adjuvant chemotherapy have demonstrated a remarkably long survival. Preliminary molecular insights on the SCP molecular landscape have demonstrated the recurrent presence of KRAS and TP53 mutations, highlighting genetic similarities with conventional pancreatic ductal adenocarcinoma (PDAC). Although the use of immunotherapy in PDAC remains an unmet challenge, recent insights indicated a potentially significant role of the PD-L1/Notch3 axis in SCP, opening new horizons for immunotherapy in this cancer subtype. In this review, we described the most important clinic-pathologic features of SCP, with a specific focus on their molecular landscape and the potential targets for precision oncology.

Identification of Targetable Liabilities in the Dynamic Metabolic Profile of EGFR-Mutant Lung Adenocarcinoma: Thinking beyond Genomics for Overcoming EGFR TKI Resistance.

The use of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) as first-line treatment in patients with lung adenocarcinoma (LUAD) harboring EGFR-activating mutations has resulted in a dramatic improvement in the management of the disease. However, the long-term clinical benefit is inevitably compromised by multiple resistance mechanisms. Accumulating evidence suggests that metabolic landscape remodeling is one of the mechanisms that EGFR-mutant LUAD cells activate, thus acquiring higher plasticity, tolerating EGFR TKI-mediated cytotoxic stress, and sustaining their oncogenic phenotype. Several metabolic pathways are upregulated in EGFR TKI-resistant models modulating the levels of numerous metabolites such as lipids, carbohydrates, and metabolic enzymes which have been suggested as potential mediators of resistance to EGFR TKIs. Moreover, metabolites have been shown to carry signals and stimulate oncogenic pathways and tumor microenvironment (TME) components such as fibroblasts, facilitating resistance to EGFR TKIs in various ways. Interestingly, metabolic signatures could function as predictive biomarkers of EGFR TKI efficacy, accurately classifying patients with EGFR-mutant LUAD. In this review, we present the identified metabolic rewiring mechanisms and how these act either independently or in concert with epigenetic or TME elements to orchestrate EGFR TKI resistance. Moreover, we discuss potential nutrient dependencies that emerge, highlighting them as candidate druggable metabolic vulnerabilities with already approved drugs which, in combination with EGFR TKIs, might counteract the solid challenge of resistance, hopefully prolonging the clinical benefit.

Harnessing the epigenome to boost immunotherapy response in non-small cell lung cancer patients.

The introduction of immune checkpoint inhibitor (ICI)-based therapy for non-oncogene addicted non-small cell lung cancer (NSCLC) has significantly transformed the treatment landscape of the disease. Inhibitors of the programmed cell death protein 1/programmed death-ligand 1 (PD-1/PD-L1) immune checkpoint axis, which were initially considered as a late-line treatment option, gradually became the standard of care as first-line treatment for subgroups of NSCLC patients. However, a significant fraction of patients either fails to respond or progresses after a partial response to ICI treatment. Thus, the identification of mechanisms responsible for innate and acquired resistance to immunotherapy within a rapidly evolving tumor microenvironment (TME) is urgently required, as is the identification of reliable predictive biomarkers beyond PD-L1 expression. The deregulation of the epigenome is a key driver of cancer initiation and progression, and it has also been shown to drive therapeutic resistance. Tumor education of infiltrating myeloid cells towards an immuno-suppressive phenotype as well as induction of T-cell dysfunction in the TME is also driven by epigenome reprogramming. As it stands and, given their dynamic nature, epigenetic changes in cancer and non-cancer cells represent an attractive target to increase immunotherapy activity in NSCLC. Accordingly, clinical trials of combinatorial immuno-epigenetic drug regimens have been associated with tumor response in previously immunotherapy-resistant NSCLC patients irrespective of their PD-L1 status. Moreover, epigenetic signatures might represent valuable theragnostic biomarkers as they can be assayed easily in liquid biopsy and provide multiple layers of information. In this review, we discuss the current knowledge regarding the dysregulated epigenetic mechanisms contributing to immunotherapy resistance in NSCLC. Although the clinical data are still maturing, we highlight the attractive perspective that the synergistic model of immuno-epigenetic strategies might overcome the current limitations of immunotherapy alone and will be translated into durable clinical benefit for a broader NSCLC population.

Physical Activity and Exercise in Lung Cancer Care: Will Promises Be Fulfilled?

Lung cancer remains the leading cause of cancer-related death worldwide. Affected patients frequently experience debilitating disease-related symptoms, including dyspnea, cough, fatigue, anxiety, depression, insomnia, and pain, despite the progresses achieved in term of treatment efficacy. Physical activity and exercise are nonpharmacological interventions that have been shown to improve fatigue, quality of life, cardiorespiratory fitness, pulmonary function, muscle mass and strength, and psychological status in patients with lung cancer. Moreover, physical fitness levels, especially cardiorespiratory endurance and muscular strength, are demonstrated to be independent predictors of survival. Nevertheless, patients with lung cancer frequently present insufficient levels of physical activity and exercise, and these may contribute to quality of life impairment, reduction in functional capacity with skeletal muscle atrophy or weakness, and worsening of symptoms, particularly dyspnea. The molecular bases underlying the potential impact of exercise on the fitness and treatment outcome of patients with lung cancer are still elusive. Counteracting specific cancer cells' acquired capabilities (hallmarks of cancer), together with preventing treatment-induced adverse events, represent main candidate mechanisms. To date, the potential impact of physical activity and exercise in lung cancer remains to be fully appreciated, and no specific exercise guidelines for patients with lung cancer are available. In this article, we perform an in-depth review of the evidence supporting physical activity and exercise in lung cancer and suggest that integrating this kind of intervention within the framework of a global, multidimensional approach, taking into account also nutritional and psychological aspects, might be the most effective strategy. IMPLICATIONS FOR PRACTICE: Although growing evidence supports the safety and efficacy of exercise in lung cancer, both after surgery and during and after medical treatments, most patients are insufficiently active or sedentary. Engaging in exercise programs is particularly arduous for patients with lung cancer, mainly because of a series of physical and psychosocial disease-related barriers (including the smoking stigma). A continuous collaboration among oncologists and cancer exercise specialists is urgently needed in order to develop tailored programs based on patients' needs, preferences, and physical and psychological status. In this regard, benefit of exercise appears to be potentially enhanced when administered as a multidimensional, comprehensive approach to patients' well-being.

PTEN in Lung Cancer: Dealing with the Problem, Building on New Knowledge and Turning the Game Around.

Lung cancer is the most common malignancy and cause of cancer deaths worldwide, owing to the dismal prognosis for most affected patients. Phosphatase and tensin homolog deleted in chromosome 10 (PTEN) acts as a powerful tumor suppressor gene and even partial reduction of its levels increases cancer susceptibility. While the most validated anti-oncogenic duty of PTEN is the negative regulation of the PI3K/mTOR/Akt oncogenic signaling pathway, further tumor suppressor functions, such as chromosomal integrity and DNA repair have been reported. PTEN protein loss is a frequent event in lung cancer, but genetic alterations are not equally detected. It has been demonstrated that its expression is regulated at multiple genetic and epigenetic levels and deeper delineation of these mechanisms might provide fertile ground for upgrading lung cancer therapeutics. Today, PTEN expression is usually determined by immunohistochemistry and low protein levels have been associated with decreased survival in lung cancer. Moreover, available data involve PTEN mutations and loss of activity with resistance to targeted treatments and immunotherapy. This review discusses the current knowledge about PTEN status in lung cancer, highlighting the prevalence of its alterations in the disease, the regulatory mechanisms and the implications of PTEN on available treatment options.

Muscle derangement and alteration of the nutritional machinery in NSCLC.

Weight loss and depletion of nutritional status are frequent presentation hallmarks in non-small cell lung cancer (NSCLC). Decline in muscle mass is a major component in weight loss and may have both a prognostic and predictive value for survival and treatment-related toxicities. Recent findings suggest that weight and skeletal muscle mass gain during treatment may represent surrogate markers for outcome in advanced NSCLC patients. Herein we present an in-depth view of the impact of nutritional status derangements on NSCLC patients' outcome, focusing on lean body mass variations during disease course. We explored the impact of malnutrition with a major attention on novel treatment options. We reviewed molecular, metabolic and immunological mechanisms underlying muscle-wasting condition, which may exhibit a meaningful targeting potential. Incorporating a specialized and accurate body composition assessment into a comprehensive, patient-centered and tailored intervention will facilitate the achievement of nutritional goals and optimal care for lung cancer patients.

PD-L1 for selecting non-small-cell lung cancer patients for first-line immuno-chemotherapy combination: a systematic review and meta-analysis.

Aim: With the final aim to explore the first-line treatment options for non-small-cell lung cancer (NSCLC) patients, we performed a systematic review and literature-based meta-analysis of available clinical trials exploring immunotherapy in combination versus standard histology-based chemotherapy. Materials & methods: We evaluated interactions according to type of treatment-add-on strategy: immunotherapy in combination versus standard chemotherapy-based regimens. Hazard ratio (HR) for overall survival (OS) and progression-free survival (PFS) were extracted and cumulated. Results: Seven trials (4278 patients) were included. The addition of immunotherapy to standard chemotherapy-based regimens significantly increased OS (HR 0.74; p = 0.001) and PFS (HR 0.61; p < 0.0001) compared with standard-of-care in NSCLC patients in first-line setting. Conclusion: Immunotherapy-based regimens constantly improved OS and PFS compared with chemotherapy in first-line treatment of nononcogene-addicted NSCLC.

Unmasking the impact of Rictor in cancer: novel insights of mTORC2 complex.

Genomic alterations affecting components of the mechanistic target of rapamycin (mTOR) pathway are found rather frequently in cancers, suggesting that aberrant pathway activity is implicated in oncogenesis of different tumor types. mTOR functions as the core catalytic kinase of two distinct complexes, mTOR complex 1 (mTORC1) and 2 (mTORC2), which control numerous vital cellular processes. There is growing evidence indicating that Rictor, an essential subunit of the mTORC2 complex, is inappropriately overexpressed across numerous cancer types and this is associated with poor survival. To date, the candidate mechanisms responsible for aberrant Rictor expression described in cancer are two: (i) gene amplification and (ii) epigenetic regulation, mainly by microRNAs. Moreover, different mTOR-independent Rictor-containing complexes with oncogenic role have been documented, revealing alternative routes of Rictor-driven tumorigenesis, but simultaneously, paving the way for identifying novel biomarkers and therapeutic targets. Here, we review the main preclinical and clinical data regarding the role of Rictor in carcinogenesis and metastatic behavior as well as the potentiality of its alteration as a target.

Putative predictors of efficacy for immune checkpoint inhibitors in non-small-cell lung cancer: facing the complexity of the immune system.

INTRODUCTION: In non-small-cell lung cancer (NSCLC) the recent introduction of immunotherapy in daily clinical practice produced a wave of enthusiasm, however, this was rapidly moderated by the evidence that only some patients could experience a relevant clinical benefit. Therefore, a great effort from the scientific community has been dedicated to the identification and validation of reliable biomarkers able to drive the activity of immunotherapeutic agents. Areas covered: This analysis aims to review the main findings about predictive biomarkers for immunotherapy in lung cancer, retracing the history of PD-L1 and focusing on a series of innovative candidates, such as mutational load, immune cell populations and microbiome. Expert commentary: Considering the complexity of the immune system-cancer interactions, the idea of identifying a single biomarker able to drive the activity of different immunotherapeutic agents alone, borrowing the idea of targeted therapy, is likely to represent an unrealistic objective. Nevertheless, the identification of those factors either positively or negatively affecting the response is mandatory in order to recruit the appropriate patients, but also to deeply understand the mechanisms of immune response and improve the clinical benefit deriving from these agents in monotherapy or in a biologically-rationale combination.

MET exon 14 juxtamembrane splicing mutations: clinical and therapeutical perspectives for cancer therapy.

The MET proto-oncogene plays crucial roles in cell growth and proliferation, survival and apoptosis, epithelial-mesenchymal transition (EMT) and invasion, potentially conditioning the development and progression of the carcinogenesis process. The MET-associated aberrant signaling could be triggered by a variety of mechanisms, such as mutations, gene amplification, increased gene copy number and Met/HGF protein expression. Among the various MET alterations, MET exon 14 splicing abnormalities, causing the loss of the Met juxtamembrane (JM) domain, recently emerged as a new potential oncogenic driver and have been identified and validated across different cancer and histology subtypes. Moreover, this aberration was found to be mutually exclusive with other recognized drivers, thus strongly nominating its potential oncogenic role. Recently, the clinical activity of anti-Met-targeted therapy was demonstrated particularly in patients harboring MET exon 14 skipping lung cancer, resulting in a renewed enthusiasm to further test MET precision therapy in prospective trials. In this review, the key preclinical and clinical data regarding MET exon 14 skipping splicing variants as an actionable genomic aberration in cancer are described, and the perspectives deriving from the validation of such alteration as a potential target, which may further allow driving the therapeutic approach in this molecularly selected patients' subgroup, are explored.