Receptor tyrosine kinases (RTKs) play an important role in a variety of cellular processes including growth, motility, differentiation, and metabolism. As such, dysregulation of RTK signaling leads ...to an assortment of human diseases, most notably, cancers. Recent large-scale genomic studies have revealed the presence of various alterations in the genes encoding RTKs such as EGFR, HER2/ErbB2, and MET, amongst many others. Abnormal RTK activation in human cancers is mediated by four principal mechanisms: gain-of-function mutations, genomic amplification, chromosomal rearrangements, and / or autocrine activation. In this manuscript, we review the processes whereby RTKs are activated under normal physiological conditions and discuss several mechanisms whereby RTKs can be aberrantly activated in human cancers. Understanding of these mechanisms has important implications for selection of anti-cancer therapies.
Lung cancer remains the leading cause of cancer-related death worldwide.
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Even in the context of early-stage disease, survival among patients with lung cancer lags behind that among patients with ...other common cancers, such as colon, breast, and prostate cancer. The likelihood of 5-year survival remains modest,
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with patients having both local or regional relapse and metastatic relapse. Although surgery with curative intent remains the foundation for management of early-stage lung cancer, these data speak to the urgent need for improvements in systemic control. With the advent of targeted therapies directed against mutant oncoproteins and immune-checkpoint inhibitors to promote host antitumor . . .
Lung cancer remains the leading cause of cancer-related deaths worldwide.
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However, the surge of new therapies and the use of these therapies in earlier stages of disease have generated tremendous ...hope for improved outcomes. In particular, immune checkpoint inhibitor therapies, with agents targeting programmed cell death protein 1 and programmed death ligand 1, administered before (neoadjuvant)
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or after (adjuvant)
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surgical resection, are now considered to be standard treatment options for patients with early-stage lung cancer. These treatments bring much-needed advances to an area of lung cancer medicine that has been in a drought for decades. Recently, several large clinical trials . . .
The development of targeted therapies has revolutionized the treatment of cancer patients. The identification of "druggable" oncogenic kinases and the creation of small-molecule inhibitors designed ...to specifically target these mutant kinases have become an important therapeutic paradigm across several different malignancies. Often these inhibitors induce dramatic clinical responses in molecularly defined cohorts. However, resistance to such targeted therapies is an inevitable consequence of this therapeutic approach. Resistance can be either primary (de novo) or acquired. Mechanisms leading to primary resistance may be categorized as tumor intrinsic factors or as patient/drug-specific factors. Acquired resistance may be mediated by target gene modification, activation of "bypass tracks" that serve as compensatory signaling loops, or histologic transformation. This brief review is a snapshot of the complex problem of therapeutic resistance, with a focus on resistance to kinase inhibitors in EGF receptor mutant and ALK rearranged non-small cell lung cancer, BRAF-mutant melanoma, and BCR-ABL-positive chronic myeloid leukemia. We describe specific mechanisms of primary and acquired resistance and then review emerging strategies to delay or overcome drug resistance.
The IGF1R signaling pathway is a complex and tightly regulated network that is critical for cell proliferation, growth, and survival. IGF1R is a potential therapeutic target for patients with many ...different malignancies. This brief review summarizes the results of clinical trials targeting the IGF1R pathway in patients with breast cancer, sarcoma, and non-small cell lung cancer (NSCLC). Therapeutic agents discussed include both monoclonal antibodies to IGF1R (dalotuzumab, figitumumab, cixutumumab, ganitumab, R1507, AVE1642) and newer IGF1R pathway targeting strategies, including monoclonal antibodies to IGF1 and IGF2 (MEDI-573 and BI 836845) and a small-molecule tyrosine kinase inhibitor of IGF1R (linsitinib). The pullback of trials in patients with breast cancer and NSCLC based on several large negative trials is noted and contrasted with the sustained success of IGF1R inhibitor monotherapy in a subset of patients with sarcoma. Several different biomarkers have been examined in these trials with varying levels of success, including tumor expression of IGF1R and its pathway components, serum IGF ligand levels, alternate pathway activation, and specific molecular signatures of IGF1R pathway dependence. However, there remains a critical need to define predictive biomarkers in order to identify patients who may benefit from IGF1R-directed therapies. Ongoing research focuses on uncovering such biomarkers and elucidating mechanisms of resistance, as this therapeutic target is currently being analyzed from the bedside to bench.
The anaplastic lymphoma kinase (ALK) receptor tyrosine kinase was initially discovered as a component of the fusion protein nucleophosmin (NPM)-ALK in anaplastic large-cell lymphoma (ALCL). Genomic ...alterations in ALK, including rearrangements, point mutations, and genomic amplification, have now been identified in several malignancies, including lymphoma, non-small cell lung cancer (NSCLC), neuroblastoma, inflammatory myofibroblastic tumor, and others. Importantly, ALK serves as a validated therapeutic target in these diseases. Several ALK tyrosine kinase inhibitors (TKI), including crizotinib, ceritinib, and alectinib, have been developed, and some of them have already been approved for clinical use. These ALK inhibitors have all shown remarkable clinical outcomes in ALK-rearranged NSCLC. Unfortunately, as is the case for other kinase inhibitors in clinical use, sensitive tumors inevitably relapse due to acquired resistance. This review focuses on the discovery, function, and therapeutic targeting of ALK, with a particular focus on ALK-rearranged NSCLC.
Knowledge of tumor mutation status is becoming increasingly important for the treatment of cancer, as mutation-specific inhibitors are being developed for clinical use that target only ...sub-populations of patients with particular tumor genotypes. Melanoma provides a recent example of this paradigm. We report here development, validation, and implementation of an assay designed to simultaneously detect 43 common somatic point mutations in 6 genes (BRAF, NRAS, KIT, GNAQ, GNA11, and CTNNB1) potentially relevant to existing and emerging targeted therapies specifically in melanoma.
The test utilizes the SNaPshot method (multiplex PCR, multiplex primer extension, and capillary electrophoresis) and can be performed rapidly with high sensitivity (requiring 5-10% mutant allele frequency) and minimal amounts of DNA (10-20 nanograms). The assay was validated using cell lines, fresh-frozen tissue, and formalin-fixed paraffin embedded tissue. Clinical characteristics and the impact on clinical trial enrollment were then assessed for the first 150 melanoma patients whose tumors were genotyped in the Vanderbilt molecular diagnostics lab.
Directing this test to a single disease, 90 of 150 (60%) melanomas from sites throughout the body harbored a mutation tested, including 57, 23, 6, 3, and 2 mutations in BRAF, NRAS, GNAQ, KIT, and CTNNB1, respectively. Among BRAF V600 mutations, 79%, 12%, 5%, and 4% were V600E, V600K, V600R, and V600M, respectively. 23 of 54 (43%) patients with mutation harboring metastatic disease were subsequently enrolled in genotype-driven trials.
We present development of a simple mutational profiling screen for clinically relevant mutations in melanoma. Adoption of this genetically-informed approach to the treatment of melanoma has already had an impact on clinical trial enrollment and prioritization of therapy for patients with the disease.
Anti-PD-1 therapy yields objective clinical responses in 30-40% of advanced melanoma patients. Since most patients do not respond, predictive biomarkers to guide treatment selection are needed. We ...hypothesize that MHC-I/II expression is required for tumour antigen presentation and may predict anti-PD-1 therapy response. In this study, across 60 melanoma cell lines, we find bimodal expression patterns of MHC-II, while MHC-I expression was ubiquitous. A unique subset of melanomas are capable of expressing MHC-II under basal or IFNγ-stimulated conditions. Using pathway analysis, we show that MHC-II(+) cell lines demonstrate signatures of 'PD-1 signalling', 'allograft rejection' and 'T-cell receptor signalling', among others. In two independent cohorts of anti-PD-1-treated melanoma patients, MHC-II positivity on tumour cells is associated with therapeutic response, progression-free and overall survival, as well as CD4(+) and CD8(+) tumour infiltrate. MHC-II(+) tumours can be identified by melanoma-specific immunohistochemistry using commercially available antibodies for HLA-DR to improve anti-PD-1 patient selection.
Purpose Advanced anaplastic lymphoma kinase ( ALK) fusion-positive non-small-cell lung cancers (NSCLCs) are effectively treated with ALK tyrosine kinase inhibitors (TKIs). However, clinical outcomes ...in these patients vary, and the benefit of TKIs is limited as a result of acquired resistance. Emerging data suggest that the ALK fusion variant may affect clinical outcome, but the molecular basis for this association is unknown. Patients and Methods We identified 129 patients with ALK-positive NSCLC with known ALK variants. ALK resistance mutations and clinical outcomes on ALK TKIs were retrospectively evaluated according to ALK variant. A Foundation Medicine data set of 577 patients with ALK-positive NSCLC was also examined. Results The most frequent ALK variants were EML4-ALK variant 1 in 55 patients (43%) and variant 3 in 51 patients (40%). We analyzed 77 tumor biopsy specimens from patients with variants 1 and 3 who had progressed on an ALK TKI. ALK resistance mutations were significantly more common in variant 3 than in variant 1 (57% v 30%; P = .023). In particular, ALK G1202R was more common in variant 3 than in variant 1 (32% v 0%; P < .001). Analysis of the Foundation Medicine database revealed similar associations of variant 3 with ALK resistance mutation and with G1202R ( P = .010 and .015, respectively). Among patients treated with the third-generation ALK TKI lorlatinib, variant 3 was associated with a significantly longer progression-free survival than variant 1 (hazard ratio, 0.31; 95% CI, 0.12 to 0.79; P = .011). Conclusion Specific ALK variants may be associated with the development of ALK resistance mutations, particularly G1202R, and provide a molecular link between variant and clinical outcome. ALK variant thus represents a potentially important factor in the selection of next-generation ALK inhibitors.
Chromosomal rearrangements involving the ROS1 receptor tyrosine kinase gene have recently been described in a subset of non-small-cell lung cancers (NSCLCs). Because little is known about these ...tumors, we examined the clinical characteristics and treatment outcomes of patients with NSCLC with ROS1 rearrangement.
Using a ROS1 fluorescent in situ hybridization (FISH) assay, we screened 1,073 patients with NSCLC and correlated ROS1 rearrangement status with clinical characteristics, overall survival, and when available, ALK rearrangement status. In vitro studies assessed the responsiveness of cells with ROS1 rearrangement to the tyrosine kinase inhibitor crizotinib. The clinical response of one patient with ROS1-rearranged NSCLC to crizotinib was investigated as part of an expanded phase I cohort.
Of 1,073 tumors screened, 18 (1.7%) were ROS1 rearranged by FISH, and 31 (2.9%) were ALK rearranged. Compared with the ROS1-negative group, patients with ROS1 rearrangements were significantly younger and more likely to be never-smokers (each P < .001). All of the ROS1-positive tumors were adenocarcinomas, with a tendency toward higher grade. ROS1-positive and -negative groups showed no difference in overall survival. The HCC78 ROS1-rearranged NSCLC cell line and 293 cells transfected with CD74-ROS1 showed evidence of sensitivity to crizotinib. The patient treated with crizotinib showed tumor shrinkage, with a near complete response.
ROS1 rearrangement defines a molecular subset of NSCLC with distinct clinical characteristics that are similar to those observed in patients with ALK-rearranged NSCLC. Crizotinib shows in vitro activity and early evidence of clinical activity in ROS1-rearranged NSCLC.
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