RAF kinase inhibitors have substantial therapeutic effects in patients with BRAF-mutant melanoma. However, only rarely do tumors regress completely, and the therapeutic effects are often temporary. ...Several mechanisms of resistance to RAF inhibitors have been proposed. The majority of these cause ERK signaling to become insensitive to treatment with RAF inhibitors by increasing the amount of RAF dimers in cells, whereas others bypass the dependence of the tumor on mutant RAF. One motivation for studying mechanisms of drug resistance is that such efforts may suggest new therapeutic targets or rational combination strategies that delay or prevent the emergence of drug-resistant clones. Here, we review the current model of RAF inhibitor resistance with a focus on the implications of this model on ongoing laboratory and clinical efforts to develop more effective therapeutic strategies for patients with BRAF-mutant tumors.
Clinical cancer genomic profiling Chakravarty, Debyani; Solit, David B
Nature reviews. Genetics,
08/2021, Letnik:
22, Številka:
8
Journal Article
Recenzirano
Technological innovation and rapid reduction in sequencing costs have enabled the genomic profiling of hundreds of cancer-associated genes as a component of routine cancer care. Tumour genomic ...profiling can refine cancer subtype classification, identify which patients are most likely to benefit from systemic therapies and screen for germline variants that influence heritable cancer risk. Here, we discuss ongoing efforts to enhance the clinical utility of tumour genomic profiling by integrating tumour and germline analyses, characterizing allelic context and identifying mutational signatures that influence therapy response. We also discuss the potential clinical utility of more comprehensive whole-genome and whole-transcriptome sequencing and ultra-sensitive cell-free DNA profiling platforms, which allow for minimally invasive, serial analyses of tumour-derived DNA in blood.
KRAS G12C inhibitors have shown promise in KRAS G12C-mutant lung cancer but intrinsic and acquired resistance are common. Cotreatment with inhibitors of the protein phosphatase SHP2 can abrogate the ...adaptive response of cancer cells to KRAS inhibitors resulting in greater suppression of MAPK signaling and enhanced tumor growth inhibition.
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Bladder cancer is the fifth most prevalent cancer in the U.S., yet is understudied, and few laboratory models exist that reflect the biology of the human disease. Here, we describe a biobank of ...patient-derived organoid lines that recapitulates the histopathological and molecular diversity of human bladder cancer. Organoid lines can be established efficiently from patient biopsies acquired before and after disease recurrence and are interconvertible with orthotopic xenografts. Notably, organoid lines often retain parental tumor heterogeneity and exhibit a spectrum of genomic changes that are consistent with tumor evolution in culture. Analyses of drug response using bladder tumor organoids show partial correlations with mutational profiles, as well as changes associated with treatment resistance, and specific responses can be validated using xenografts in vivo. Our studies indicate that patient-derived bladder tumor organoids represent a faithful model system for studying tumor evolution and treatment response in the context of precision cancer medicine.
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•Efficient generation of a biobank of patient-derived bladder cancer organoids•Organoids recapitulate the histological and molecular spectrum of human bladder cancer•Bladder tumor organoids display clonal evolution in culture and as xenografts•Drug response of organoids can be validated in xenografts
A biobank of patient-derived bladder tumor organoids faithfully recapitulates features of human cancer and enables analysis of clonal evolution and drug responses.
Various genetic driver aberrations have been identified among distinct anatomic and clinical subtypes of intrahepatic and extrahepatic cholangiocarcinoma, and these molecular alterations may be ...prognostic biomarkers and/or predictive of drug response.
Tumor samples from patients with cholangiocarcinoma who consented prospectively were analyzed using the MSK-IMPACT platform, a targeted next-generation sequencing assay that analyzes all exons and selected introns of 410 cancer-associated genes. Fisher exact tests were performed to identify associations between clinical characteristics and genetic alterations.
A total of 195 patients were studied: 78% intrahepatic and 22% extrahepatic cholangiocarcinoma. The most commonly altered genes in intrahepatic cholangiocarcinoma were
(30%),
(23%),
(20%),
(20%), and
gene fusions (14%). A tendency toward mutual exclusivity was seen between multiple genes in intrahepatic cholangiocarcinoma including
, and
Alterations in CDKN2A/B and ERBB2 were associated with reduced survival and time to progression on chemotherapy in patients with locally advanced or metastatic disease. Genetic alterations with potential therapeutic implications were identified in 47% of patients, leading to biomarker-directed therapy or clinical trial enrollment in 16% of patients.
Cholangiocarcinoma is a genetically diverse cancer. Alterations in
and
are associated with negative prognostic implications in patients with advanced disease. Somatic alterations with therapeutic implications were identified in almost half of patients. These prospective data provide a contemporary benchmark for guiding the development of targeted therapies in molecularly profiled cholangiocarcinoma, and support to the use of molecular profiling to guide therapy selection in patients with advanced biliary cancers.
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Addition of trastuzumab to first-line chemotherapy improves overall survival in patients with HER2-positive metastatic gastric cancer. We assessed the safety and activity of pembrolizumab in ...combination with trastuzumab and chemotherapy in first-line HER2-positive metastatic oesophagogastric (gastric, oesophageal, or gastroesophageal junction) cancer.
This study was an investigator-initiated, open-label, non-randomised, single-arm, single centre, phase 2 trial in patients aged 18 years or older with HER2-positive metastatic oesophagogastric cancer. Eligible patients had measurable or evaluable non-measurable disease, Eastern Cooperative Oncology Group performance status of 0, 1, or 2, and left ventricular ejection fraction of at least 53%. Patients were eligible to receive an initial induction cycle of 200 mg flat dose of intravenous pembrolizumab and 8 mg/kg loading dose of intravenous trastuzumab. For subsequent cycles, patients received 130 mg/m2 of intravenous oxaliplatin or 80 mg/m2 of cisplatin on day 1, 850 mg/m2 of oral capecitabine twice a day for 2 weeks followed by 1 week off (or intravenous 5-fluorouracil, 800 mg/m2 per day on days 1–5), and a 200 mg flat dose of intravenous pembrolizumab, and 6 mg/kg of trastuzumab, administered on day 1 of each 3-week cycle. The primary endpoint was 6-month progression-free survival, defined as the proportion of patients alive and free of progression at 6 months, assessed in patients who received at least one dose of trastuzumab and pembrolizumab. The regimen would be considered worthy of further investigation if 26 or more of 37 patients were progression-free at 6 months. This trial is registered with ClinicalTrials.gov, NCT02954536, and is ongoing, but closed to enrolment.
Between Nov 11, 2016, and Jan 23, 2019, 37 patients were enrolled. At the time of data cutoff on Aug 6, 2019, median follow-up among survivors was 13·0 months (IQR 11·7–23·5). The primary endpoint was achieved; 26 (70%; 95% CI 54–83) of 37 patients were progression-free at 6 months. The most common treatment-related adverse event of any grade was neuropathy, which was reported in 36 (97%) of 37 patients. The most common grade 3 or 4 adverse events were lymphocytopenia (seven 19% patients with grade 3 and two 5% with grade 4), grade 3 decreased electrolytes (six 16% patients), and grade 3 anaemia (four 11% patients). Serious adverse events occurred in two patients patients (both grade 3 nephritis leading to treatment discontinuation). Four patients discontinued pembrolizumab because of immune-related adverse events. There were no treatment-related deaths.
Pembrolizumab can be safely combined with trastuzumab and chemotherapy and has promising activity in HER2-positive metastatic oesophagogastric cancer. A randomised phase 3 clinical trial assessing the efficacy and safety of pembrolizumab versus placebo in combination with trastuzumab and chemotherapy in first-line HER2-positive metastatic oesophagogastric cancer is underway.
Merck & Co.
Prior molecular profiling of hepatocellular carcinoma (HCC) has identified actionable findings that may have a role in guiding therapeutic decision-making and clinical trial enrollment. We ...implemented prospective next-generation sequencing (NGS) in the clinic to determine whether such analyses provide predictive and/or prognostic information for HCC patients treated with contemporary systemic therapies.
Matched tumor/normal DNA from patients with HCC (
= 127) were analyzed using a hybridization capture-based NGS assay designed to target 341 or more cancer-associated genes. Demographic and treatment data were prospectively collected with the goal of correlating treatment outcomes and drug response with molecular profiles.
WNT/β-catenin pathway (45%) and
(33%) alterations were frequent and represented mutually exclusive molecular subsets. In sorafenib-treated patients (
= 81), oncogenic PI3K-mTOR pathway alterations were associated with lower disease control rates (DCR, 8.3% vs. 40.2%), shorter median progression-free survival (PFS; 1.9 vs. 5.3 months), and shorter median overall survival (OS; 10.4 vs. 17.9 months). For patients treated with immune checkpoint inhibitors (
= 31), activating alteration WNT/β-catenin signaling were associated with lower DCR (0% vs. 53%), shorter median PFS (2.0 vs. 7.4 months), and shorter median OS (9.1 vs. 15.2 months). Twenty-four percent of patients harbored potentially actionable alterations including
(8.5%) inactivating/truncating mutations,
(6.3%) and
(1.5%) amplifications, and
missense mutations (<1%). Six percent of patients treated with systemic therapy were matched to targeted therapeutics.
Linking NGS to routine clinical care has the potential to identify those patients with HCC likely to benefit from standard systemic therapies and can be used in an investigational context to match patients to genome-directed targeted therapies.
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Mutational hotspots indicate selective pressure across a population of tumor samples, but their prevalence within and across cancer types is incompletely characterized. An approach to detect ...significantly mutated residues, rather than methods that identify recurrently mutated genes, may uncover new biologically and therapeutically relevant driver mutations. Here, we developed a statistical algorithm to identify recurrently mutated residues in tumor samples. We applied the algorithm to 11,119 human tumors, spanning 41 cancer types, and identified 470 somatic substitution hotspots in 275 genes. We find that half of all human tumors possess one or more mutational hotspots with widespread lineage-, position- and mutant allele-specific differences, many of which are likely functional. In total, 243 hotspots were novel and appeared to affect a broad spectrum of molecular function, including hotspots at paralogous residues of Ras-related small GTPases RAC1 and RRAS2. Redefining hotspots at mutant amino acid resolution will help elucidate the allele-specific differences in their function and could have important therapeutic implications.
ERK signaling requires RAS-induced RAF dimerization and is limited by feedback. Activated BRAF mutants evade feedback inhibition of RAS by either of two mechanisms. BRAF V600 mutants are activated ...monomers when RAS activity is low; all other activating BRAF mutants function as constitutive RAS-independent dimers. RAF inhibitors effectively inhibit mutant monomers, but not dimers; their binding to one site in the dimer significantly reduces their affinity for the second. Tumors with non-V600E BRAF mutants are insensitive to these drugs, and increased expression of BRAF V600E dimers causes acquired resistance. A compound that equally inhibits both sites of mutant RAF dimers inhibits tumors driven by either class of mutants or those BRAF V600E tumors with dimer-dependent acquired resistance to monomer-specific inhibitors.
•All activating BRAF mutants are RAS independent•Activating BRAF mutants signal as active monomers or constitutive dimers•RAF dimers are insensitive to clinical RAF inhibitors due to negative cooperativity•A compound that equally inhibits mutant BRAF monomers and dimers overcomes resistance
Yao et al. show that RAS-independence is a common property of activating BRAF mutants that occurs by either of two mechanisms. Active monomers are sensitive to current drugs, whereas constitutive dimers are not. A compound that equally binds both sites of dimers is active against all activated BRAF mutants and overcomes acquired resistance to current drugs.
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