MET or hepatocyte growth factor (HGF) receptor pathway signaling mediates wound healing and hepatic regeneration, with pivotal roles in embryonic, neuronal, and muscle development. However, ...dysregulation of MET signaling mediates proliferation, apoptosis, and migration and is implicated in a number of malignancies. In non-small cell lung cancer (NSCLC), aberrant MET signaling can occur through a number of mechanisms that collectively represent a significant proportion of patients. These include MET or HGF protein overexpression,
gene amplification,
gene mutation or fusion/rearrangement, or aberrations in downstream signaling or regulatory components. Responses to MET tyrosine kinase inhibitors have been documented in clinical trials in patients with
-amplified or MET-overexpressing NSCLC, and case studies or case series have shown that
mutation/deletion is a biomarker that is also predictive of response to these agents. However, other recent clinical data have highlighted an urgent need to elucidate optimal biomarkers based on genetic and/or protein diagnostics to correctly identify patients most likely to benefit in ongoing clinical trials of an array of MET-targeted therapies of differing class. The latest advances in the development of MET biomarkers in NSCLC have been reviewed, toward establishing appropriate MET biomarker selection based on a scientific rationale.
.
Drug resistance is a serious impediment to the treatment of cancer. However, the mechanisms involved remain poorly understood. While it is widely held that the phenomenon is genetic in nature, ...emerging evidence suggests that non-genetic mechanisms may also be important. Furthermore, at least in some cases, refractoriness to treatment can be reversed by epigenetic reprogramming, and combination and intermittent therapies, as opposed to sustained monotherapy, appear more effective in attenuating it. Here we iterate the confusion in understanding the phenomenon by which cancer cells evade drug response and underscore the need to recognize the genetic/non-genetic duality of drug resistance in cancer. We discuss how ecological and evolutionary principles may help to reconcile the duality and may even offer new treatment strategies.
Early preclinical evidence provided the rationale for programmed cell death 1 (PD-1) and programmed death ligand 1 (PD-L1) blockade as a potential form of cancer immunotherapy given that activation ...of the PD-1/PD-L1 axis putatively served as a mechanism for tumor evasion of host tumor antigen-specific T-cell immunity. Early-phase studies investigating several humanized monoclonal IgG4 antibodies targeting PD-1 and PD-L1 in advanced solid tumors paved way for the development of the first PD-1 inhibitors, nivolumab and pembrolizumab, approved by the Food and Drug Administration (FDA) in 2014. The number of FDA-approved agents of this class is rapidly enlarging with indications for treatment spanning across a spectrum of malignancies. The purpose of this review is to highlight the clinical development of PD-1 and PD-L1 inhibitors in cancer therapy to date. In particular, we focus on detailing the registration trials that have led to FDA-approved indications of anti-PD-1 and anti-PD-L1 therapies in cancer. As the number of PD-1/PD-L1 inhibitors continues to grow, predictive biomarkers, mechanisms of resistance, hyperprogressors, treatment duration and treatment beyond progression, immune-related toxicities, and clinical trial design are key concepts in need of further consideration to optimize the anticancer potential of this class of immunotherapy.
Mitochondria have emerged as important pharmacological targets because of their key role in cellular proliferation and death. In tumor tissues, mitochondria can switch metabolic phenotypes to meet ...the challenges of high energy demand and macromolecular synthesis. Furthermore, mitochondria can engage in crosstalk with the tumor microenvironment, and signals from cancer-associated fibroblasts can impinge on mitochondria. Cancer cells can also acquire a hybrid phenotype in which both glycolysis and oxidative phosphorylation (OXPHOS) can be utilized. This hybrid phenotype can facilitate metabolic plasticity of cancer cells more specifically in metastasis and therapy-resistance. In light of the metabolic heterogeneity and plasticity of cancer cells that had until recently remained unappreciated, strategies targeting cancer metabolic dependency appear to be promising in the development of novel and effective cancer therapeutics.
Mitochondria display a dynamic and heterogeneous phenotype that facilitates the metabolic heterogeneity and plasticity of cancer cells. The altered metabolic functions and dynamics of mitochondria in cancer cells, as well as mitochondrial evasion of apoptosis, provide targets for novel cancer therapeutics.The mitochondrial network has distinct morphological features that appear to be interrelated with mitochondrial dynamics. Fractal measurements to evaluate the mitochondrial network alongside the metabolic profile of tumors may provide insight into tumor sensitivity to mitochondrial therapeutics.Although there are a few FDA-approved cancer-directed therapies that specifically target mitochondria, numerous therapies have been evaluated in clinical trials that target mitochondrial metabolism and evasion of apoptosis, with promising results in a variety of cancer types.
Lung cancer is a heterogeneous group of disorders that is now being subdivided into molecular subtypes with dedicated targeted therapies. The MET receptor tyrosine kinase has been identified as ...aberrantly overexpressed, potentially having activating mutations, and amplified in certain subsets of lung cancers. The ligand hepatocyte growth factor (HGF) can also be overexpressed in lung cancer or expressed in stroma, and both the MET receptor and the HGF ligand can be targets for therapeutics, especially in lung cancer. Activation of MET leads to a plethora of biochemical and biologic changes both in normal and cancerous cells. Preclinically, it has been shown that silencing or inactivating MET leads to decreased viability of cancer cells. There are a number of compounds against MET/HGF in clinical trials that have been shown to be active in lung cancers. This review will summarize the biology of MET as well as its therapeutic inhibition in lung cancer.
Summary Background Anaplastic lymphoma kinase ( ALK ) gene rearrangements are oncogenic drivers of non-small-cell lung cancer (NSCLC). Brigatinib (AP26113) is an investigational ALK inhibitor with ...potent preclinical activity against ALK mutants resistant to crizotinib and other ALK inhibitors. We aimed to assess brigatinib in patients with advanced malignancies, particularly ALK -rearranged NSCLC. Methods In this ongoing, single-arm, open-label, phase 1/2 trial, we recruited patients from nine academic hospitals or cancer centres in the USA and Spain. Eligible patients were at least 18 years of age and had advanced malignancies, including ALK -rearranged NSCLC, and disease that was refractory to available therapies or for which no curative treatments existed. In the initial dose-escalation phase 1 stage of the trial, patients received oral brigatinib at total daily doses of 30–300 mg (according to a standard 3 + 3 design). The phase 1 primary endpoint was establishment of the recommended phase 2 dose. In the phase 2 expansion stage, we assessed three oral once-daily regimens: 90 mg, 180 mg, and 180 mg with a 7 day lead-in at 90 mg; one patient received 90 mg twice daily. We enrolled patients in phase 2 into five cohorts: ALK inhibitor-naive ALK -rearranged NSCLC (cohort 1), crizotinib-treated ALK -rearranged NSCLC (cohort 2), EGFRT790M -positive NSCLC and resistance to one previous EGFR tyrosine kinase inhibitor (cohort 3), other cancers with abnormalities in brigatinib targets (cohort 4), and crizotinib-naive or crizotinib-treated ALK -rearranged NSCLC with active, measurable, intracranial CNS metastases (cohort 5). The phase 2 primary endpoint was the proportion of patients with an objective response. Safety and activity of brigatinib were analysed in all patients in both phases of the trial who had received at least one dose of treatment. This trial is registered with ClinicalTrials.gov , number NCT01449461. Findings Between Sept 20, 2011, and July 8, 2014, we enrolled 137 patients (79 58% with ALK -rearranged NSCLC), all of whom were treated. Dose-limiting toxicities observed during dose escalation included grade 3 increased alanine aminotransferase (240 mg daily) and grade 4 dyspnoea (300 mg daily). We initially chose a dose of 180 mg once daily as the recommended phase 2 dose; however, we also assessed two additional regimens (90 mg once daily and 180 mg once daily with a 7 day lead-in at 90 mg) in the phase 2 stage. four (100% 95% CI 40–100) of four patients in cohort 1 had an objective response, 31 (74% 58–86) of 42 did in cohort 2, none (of one) did in cohort 3, three (17% 4–41) of 18 did in cohort 4, and five (83% 36–100) of six did in cohort 5. 51 (72% 60–82) of 71 patients with ALK -rearranged NSCLC with previous crizotinib treatment had an objective response (44 62% (50–73) had a confirmed objective response). All eight crizotinib-naive patients with ALK -rearranged NSCLC had a confirmed objective response (100% 63–100). Three (50% 95% CI 12–88) of six patients in cohort 5 had an intracranial response. The most common grade 3–4 treatment-emergent adverse events across all doses were increased lipase concentration (12 9% of 137), dyspnoea (eight 6%), and hypertension (seven 5%). Serious treatment-emergent adverse events (excluding neoplasm progression) reported in at least 5% of all patients were dyspnoea (ten 7%), pneumonia (nine 7%), and hypoxia (seven 5%). 16 (12%) patients died during treatment or within 31 days of the last dose of brigatinib, including eight patients who died from neoplasm progression. Interpretation Brigatinib shows promising clinical activity and has an acceptable safety profile in patients with crizotinib-treated and crizotinib-naive ALK -rearranged NSCLC. These results support its further development as a potential new treatment option for patients with advanced ALK -rearranged NSCLC. A randomised phase 2 trial in patients with crizotinib-resistant ALK -rearranged NSCLC is prospectively assessing the safety and efficacy of two regimens assessed in the phase 2 portion of this trial (90 mg once daily and 180 mg once daily with a 7 day lead-in at 90 mg). Funding ARIAD Pharmaceuticals.
KRAS is a frequent oncogenic driver in solid tumors, including non-small cell lung cancer (NSCLC). It was previously thought to be an “undruggable” target due to the lack of deep binding pockets for ...specific small-molecule inhibitors. A better understanding of the mechanisms that drive KRAS transformation, improved KRAS-targeted drugs, and immunological approaches that aim at yielding immune responses against KRAS neoantigens have sparked a race for approved therapies. Few treatments are available for KRAS mutant NSCLC patients, and several approaches are being tested in clinicals trials to fill this void. Here, we review promising therapeutics tested for KRAS mutant NSCLC.
Display omitted
KRAS, an oncogenic driver in lung cancer, is known as an “undruggable” targetDifferent strategies are under investigation to indirectly and directly target KRASClinical trials of small-molecule inhibitors report promising interim results
In this review, Salgia et al. discusses KRAS, a prominent oncogenic driver in lung cancer that is notoriously difficult to target. Studies have shown preclinical rationale in leveraging neoantigens and inhibiting KRAS signaling pathways in KRAS-mutant cancers. Recent advancements in clinical trials have demonstrated encouraging results with small-molecule inhibitors.
Objective Lung cancer is the leading cause of cancer death in North America. Low-dose computed tomography screening can reduce lung cancer–specific mortality by 20%. Method The American Association ...for Thoracic Surgery created a multispecialty task force to create screening guidelines for groups at high risk of developing lung cancer and survivors of previous lung cancer. Results The American Association for Thoracic Surgery guidelines call for annual lung cancer screening with low-dose computed tomography screening for North Americans from age 55 to 79 years with a 30 pack-year history of smoking. Long-term lung cancer survivors should have annual low-dose computed tomography to detect second primary lung cancer until the age of 79 years. Annual low-dose computed tomography lung cancer screening should be offered starting at age 50 years with a 20 pack-year history if there is an additional cumulative risk of developing lung cancer of 5% or greater over the following 5 years. Lung cancer screening requires participation by a subspecialty-qualified team. The American Association for Thoracic Surgery will continue engagement with other specialty societies to refine future screening guidelines. Conclusions The American Association for Thoracic Surgery provides specific guidelines for lung cancer screening in North America.
About 1% of non–small-cell lung cancers have
ROS1
rearrangements. This oncogene is inhibited by crizotinib. In a cohort of 50 patients with
ROS1
-rearranged lung cancer, crizotinib induced responses ...in 72%; the median duration of response was nearly a year and a half.
The
ROS1
oncogene encodes an orphan receptor tyrosine kinase related to anaplastic lymphoma kinase (ALK), along with members of the insulin-receptor family.
1
First discovered as the oncogene product of an avian sarcoma RNA tumor virus,
2
–
4
ROS1 (ROS1 proto-oncogene receptor tyrosine kinase) is activated by chromosomal rearrangement in a variety of human cancers, including non–small-cell lung cancer (NSCLC), cholangiocarcinoma, gastric cancer, ovarian cancer, and glioblastoma multiforme.
5
–
9
Rearrangement leads to fusion of a portion of ROS1 that includes the entire tyrosine kinase domain with 1 of 12 different partner proteins.
10
The resulting ROS1 fusion kinases are constitutively activated and drive . . .
Lung cancer (LC) is a heterogeneous disease consisting mainly of two subtypes, non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC), and remains the leading cause of death worldwide. ...Despite recent advances in therapies, the overall 5-year survival rate of LC remains less than 20%. The efficacy of current therapeutic approaches is compromised by inherent or acquired drug-resistance and severe off-target effects. Therefore, the identification and development of innovative and effective therapeutic approaches are critically desired for LC. The development of RNA-mediated gene inhibition technologies was a turning point in the field of RNA biology. The critical regulatory role of different RNAs in multiple cancer pathways makes them a rich source of targets and innovative tools for developing anticancer therapies. The identification of antisense sequences, short interfering RNAs (siRNAs), microRNAs (miRNAs or miRs), anti-miRs, and mRNA-based platforms holds great promise in preclinical and early clinical evaluation against LC. In the last decade, RNA-based therapies have substantially expanded and tested in clinical trials for multiple malignancies, including LC. This article describes the current understanding of various aspects of RNA-based therapeutics, including modern platforms, modifications, and combinations with chemo-/immunotherapies that have translational potential for LC therapies.
PDF
