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In their recent paper published in Nature, Luo et al.1 investigate the cancer-cell-intrinsic roles of the PI3Kγ complex in leukemia. Their findings pinpoint PI3Kγ inhibition as a possible novel treatment avenue for a subset of acute leukemias.
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Fosfatidilinositol 3-Quinasa Clase Ib , Leucemia , Inhibidores de las Quinasa Fosfoinosítidos-3 , Humanos , Fosfatidilinositol 3-Quinasa Clase Ib/metabolismo , Leucemia/tratamiento farmacológico , Leucemia/patología , Leucemia/metabolismo , Inhibidores de las Quinasa Fosfoinosítidos-3/farmacología , Inhibidores de las Quinasa Fosfoinosítidos-3/química , Inhibidores de las Quinasa Fosfoinosítidos-3/uso terapéutico , Antineoplásicos/farmacología , Antineoplásicos/química , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/químicaRESUMEN
PURPOSE: Medication nonadherence is common among patients with breast cancer (BC) and increases BC mortality and complications from comorbidities. There is growing interest in mobile health interventions such as smartphone applications (apps) to promote adherence. METHODS: Use of Medisafe, a medication reminder and tracking app, was tested over 12 weeks among patients on BC treatment and at least one oral medication. Study participants were instructed to generate adherence reports every 4 weeks through Medisafe and were deemed to have completed the intervention if >50% of reports were generated. The primary end point was feasibility of the intervention, defined as a completion rate of ≥75% of consented patients. Secondary end points included changes in self-reported nonadherence from baseline to 12 weeks and patient-reported outcomes including reasons for nonadherence and satisfaction with Medisafe. We conducted univariable and multivariable analyses to evaluate demographic and clinical factors associated with intervention completion. RESULTS: Among 100 patients enrolled, 78 (78.0%) completed the intervention. Age, race, ethnicity, clinical stage, and type of medication were not associated with odds of intervention completion. Self-reported nonadherence rates did not improve from baseline to postintervention in the overall study population. However, among patients with self-reported nonadherence at baseline, 26.3% reported adherence postintervention; these patients frequently reported logistical barriers to adherence. Study participants reported high levels of satisfaction with Medisafe, noting that the app was highly functional and provided high-quality information. CONCLUSION: Smartphone apps such as Medisafe are feasible and associated with high patient satisfaction. They may improve adherence in nonadherent patients and those who face logistical challenges interfering with medication-taking. Future trials of mobile health interventions should target patients at high risk for medication nonadherence.
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Single-nucleotide variants (SNVs) in key T cell genes can drive clinical pathologies and could be repurposed to improve cellular cancer immunotherapies. Here, we perform massively parallel base-editing screens to generate thousands of variants at gene loci annotated with known or potential clinical relevance. We discover a broad landscape of putative gain-of-function (GOF) and loss-of-function (LOF) mutations, including in PIK3CD and the gene encoding its regulatory subunit, PIK3R1, LCK, SOS1, AKT1 and RHOA. Base editing of PIK3CD and PIK3R1 variants in T cells with an engineered T cell receptor specific to a melanoma epitope or in different generations of CD19 chimeric antigen receptor (CAR) T cells demonstrates that discovered GOF variants, but not LOF or silent mutation controls, enhanced signaling, cytokine production and lysis of cognate melanoma and leukemia cell models, respectively. Additionally, we show that generations of CD19 CAR T cells engineered with PIK3CD GOF mutations demonstrate enhanced antigen-specific signaling, cytokine production and leukemia cell killing, including when benchmarked against other recent strategies.
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Phosphorylation of proteins on tyrosine (Tyr) residues evolved in metazoan organisms as a mechanism of coordinating tissue growth1. Multicellular eukaryotes typically have more than 50 distinct protein Tyr kinases that catalyse the phosphorylation of thousands of Tyr residues throughout the proteome1-3. How a given Tyr kinase can phosphorylate a specific subset of proteins at unique Tyr sites is only partially understood4-7. Here we used combinatorial peptide arrays to profile the substrate sequence specificity of all human Tyr kinases. Globally, the Tyr kinases demonstrate considerable diversity in optimal patterns of residues surrounding the site of phosphorylation, revealing the functional organization of the human Tyr kinome by substrate motif preference. Using this information, Tyr kinases that are most compatible with phosphorylating any Tyr site can be identified. Analysis of mass spectrometry phosphoproteomic datasets using this compendium of kinase specificities accurately identifies specific Tyr kinases that are dysregulated in cells after stimulation with growth factors, treatment with anti-cancer drugs or expression of oncogenic variants. Furthermore, the topology of known Tyr signalling networks naturally emerged from a comparison of the sequence specificities of the Tyr kinases and the SH2 phosphotyrosine (pTyr)-binding domains. Finally we show that the intrinsic substrate specificity of Tyr kinases has remained fundamentally unchanged from worms to humans, suggesting that the fidelity between Tyr kinases and their protein substrate sequences has been maintained across hundreds of millions of years of evolution.
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Fosfotirosina , Proteínas Tirosina Quinasas , Especificidad por Sustrato , Tirosina , Animales , Humanos , Secuencias de Aminoácidos , Evolución Molecular , Espectrometría de Masas , Fosfoproteínas/química , Fosfoproteínas/metabolismo , Fosforilación , Fosfotirosina/metabolismo , Proteínas Tirosina Quinasas/efectos de los fármacos , Proteínas Tirosina Quinasas/metabolismo , Proteoma/química , Proteoma/metabolismo , Proteómica , Transducción de Señal , Dominios Homologos src , Tirosina/metabolismo , Tirosina/químicaRESUMEN
The phosphoinositide 3-kinase p110α is an essential mediator of insulin signaling and glucose homeostasis. We interrogated the human serine, threonine, and tyrosine kinome to search for novel regulators of p110α and found that the Hippo kinases phosphorylate p110α at T1061, which inhibits its activity. This inhibitory state corresponds to a conformational change of a membrane-binding domain on p110α, which impairs its ability to engage membranes. In human primary hepatocytes, cancer cell lines, and rodent tissues, activation of the Hippo kinases MST1/2 using forskolin or epinephrine is associated with phosphorylation of T1061 and inhibition of p110α, impairment of downstream insulin signaling, and suppression of glycolysis and glycogen synthesis. These changes are abrogated when MST1/2 are genetically deleted or inhibited with small molecules or if the T1061 is mutated to alanine. Our study defines an inhibitory pathway of PI3K signaling and a link between epinephrine and insulin signaling.
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Proteínas Serina-Treonina Quinasas , Humanos , Animales , Ratones , Línea Celular , Ratones Endogámicos C57BL , Masculino , Femenino , Epinefrina/farmacología , Activación Enzimática/efectos de los fármacos , Proteínas Serina-Treonina Quinasas/química , Proteínas Serina-Treonina Quinasas/genética , Proteínas Serina-Treonina Quinasas/metabolismo , Fosfatidilinositoles/química , Fosfatidilinositoles/metabolismo , Eliminación de Gen , Colforsina/farmacología , Insulina/metabolismo , Fosforilación/efectos de los fármacos , Vía de Señalización Hippo/efectos de los fármacos , Vía de Señalización Hippo/genéticaRESUMEN
SUMMARY: This is the first peer-reviewed report of an allosteric, mutant-selective PI3Kα inhibitor, STX-478, that reduces PIK3CA-mutant tumor growth in mice. However, in contrast to the FDA-approved PI3Kα isoform-selective inhibitor alpelisib, STX-478 does not induce hyperglycemia or other metabolic dysfunctions. See related article by Buckbinder et al., p. 2432 (7).
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Neoplasias , Animales , Ratones , Fosfatidilinositol 3-Quinasa Clase I/genética , Neoplasias/tratamiento farmacológico , Neoplasias/genéticaRESUMEN
The cell-autonomous balance of immune-inhibitory and -stimulatory signals is a critical process in cancer immune evasion. Using patient-derived co-cultures, humanized mouse models, and single-cell RNA-sequencing of patient melanomas biopsied before and on immune checkpoint blockade, we find that intact cancer cell-intrinsic expression of CD58 and ligation to CD2 is required for anti-tumor immunity and is predictive of treatment response. Defects in this axis promote immune evasion through diminished T cell activation, impaired intratumoral T cell infiltration and proliferation, and concurrently increased PD-L1 protein stabilization. Through CRISPR-Cas9 and proteomics screens, we identify and validate CMTM6 as critical for CD58 stability and upregulation of PD-L1 upon CD58 loss. Competition between CD58 and PD-L1 for CMTM6 binding determines their rate of endosomal recycling over lysosomal degradation. Overall, we describe an underappreciated yet critical axis of cancer immunity and provide a molecular basis for how cancer cells balance immune inhibitory and stimulatory cues.
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Antígeno B7-H1 , Melanoma , Ratones , Animales , Antígeno B7-H1/genética , Linfocitos T , Antígenos CD58/química , Antígenos CD58/metabolismo , Melanoma/genética , Melanoma/metabolismo , Activación de LinfocitosRESUMEN
PURPOSE: To comprehensively characterize tissue-specific and molecular subclasses of multiple PIK3CA (multi-PIK3CA) mutations and assess their impact on potential therapeutic outcomes. EXPERIMENTAL DESIGN: We profiled a pan-cancer cohort comprised of 352,392 samples across 66 tumor types using a targeted hybrid capture-based next-generation sequencing panel covering at least 324 cancer-related genes. Molecularly defined subgroups, allelic configuration, clonality, and mutational signatures were identified and tested for association with PI3K inhibitor therapeutic response. RESULTS: Multi-PIK3CA mutations are found in 11% of all PIK3CA-mutant tumors, including 9% of low tumor mutational burden (TMB) PIK3CA-mutant tumors, and are enriched in breast and gynecologic cancers. Multi-PIK3CA mutations are frequently clonal and in cis on the same allele and occur at characteristic positions across tumor types. These mutations tend to be mutually exclusive of mutations in other driver genes, and of genes in the PI3K pathway. Among PIK3CA-mutant tumors with a high TMB, 18% are multi-PIK3CA mutant and often harbor an apolipoprotein B mRNA-editing enzyme, catalytic polypeptide (APOBEC) mutational signature. Despite large differences in specific allele combinations comprising multi-PIK3CA mutant tumors, especially across cancer types, patients with different classes of multi-PIK3CA mutant estrogen receptor-positive, HER2-negative breast cancers respond similarly to PI3K inhibition. CONCLUSIONS: Our pan-tumor study provides biological insights into the genetic heterogeneity and tissue specificities of multi-PIK3CA mutations, with potential clinical utility to guide PI3K inhibition strategies.
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Neoplasias de la Mama , Fosfatidilinositol 3-Quinasas , Humanos , Femenino , Fosfatidilinositol 3-Quinasas/genética , Heterogeneidad Genética , Neoplasias de la Mama/patología , Mutación , Fosfatidilinositol 3-Quinasa Clase I/genéticaRESUMEN
Protein phosphorylation is one of the most widespread post-translational modifications in biology1,2. With advances in mass-spectrometry-based phosphoproteomics, 90,000 sites of serine and threonine phosphorylation have so far been identified, and several thousand have been associated with human diseases and biological processes3,4. For the vast majority of phosphorylation events, it is not yet known which of the more than 300 protein serine/threonine (Ser/Thr) kinases encoded in the human genome are responsible3. Here we used synthetic peptide libraries to profile the substrate sequence specificity of 303 Ser/Thr kinases, comprising more than 84% of those predicted to be active in humans. Viewed in its entirety, the substrate specificity of the kinome was substantially more diverse than expected and was driven extensively by negative selectivity. We used our kinome-wide dataset to computationally annotate and identify the kinases capable of phosphorylating every reported phosphorylation site in the human Ser/Thr phosphoproteome. For the small minority of phosphosites for which the putative protein kinases involved have been previously reported, our predictions were in excellent agreement. When this approach was applied to examine the signalling response of tissues and cell lines to hormones, growth factors, targeted inhibitors and environmental or genetic perturbations, it revealed unexpected insights into pathway complexity and compensation. Overall, these studies reveal the intrinsic substrate specificity of the human Ser/Thr kinome, illuminate cellular signalling responses and provide a resource to link phosphorylation events to biological pathways.
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Fosfoproteínas , Proteínas Serina-Treonina Quinasas , Proteoma , Serina , Treonina , Humanos , Fosforilación , Proteínas Serina-Treonina Quinasas/metabolismo , Serina/metabolismo , Especificidad por Sustrato , Treonina/metabolismo , Proteoma/química , Proteoma/metabolismo , Conjuntos de Datos como Asunto , Fosfoproteínas/química , Fosfoproteínas/metabolismo , Línea Celular , Fosfoserina/metabolismo , Fosfotreonina/metabolismoRESUMEN
Base editing enables generation of single nucleotide variants, but large-scale screening in primary human T cells is limited due to low editing efficiency, among other challenges 1 . Here, we developed a high-throughput approach for high-efficiency and massively parallel adenine and cytosine base-editor screening in primary human T cells. We performed multiple large-scale screens editing 102 genes with central functions in T cells and full-length tiling mutagenesis of selected genes, and read out variant effects on hallmarks of T cell anti-tumor immunity, including activation, proliferation, and cytokine production. We discovered a broad landscape of gain- and loss-of-function mutations, including in PIK3CD and its regulatory subunit encoded by PIK3R1, LCK , AKT1, CTLA-4 and JAK1 . We identified variants that affected several (e.g., PIK3CD C416R) or only selected (e.g. LCK Y505C) hallmarks of T cell activity, and functionally validated several hits by probing downstream signaling nodes and testing their impact on T cell polyfunctionality and proliferation. Using primary human T cells in which we engineered a T cell receptor (TCR) specific to a commonly presented tumor testis antigen as a model for cellular immunotherapy, we demonstrate that base edits identified in our screens can tune specific or broad T cell functions and ultimately improve tumor elimination while exerting minimal off-target activity. In summary, we present the first large-scale base editing screen in primary human T cells and provide a framework for scalable and targeted base editing at high efficiency. Coupled with multi-modal phenotypic mapping, we accurately nominate variants that produce a desirable T cell state and leverage these synthetic proteins to improve models of cellular cancer immunotherapies.
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Numerous agents targeting various phosphatidylinositol 3-kinase (PI3K) pathway components, including PI3K, AKT and mTOR, have been tested in oncology clinical trials, resulting in regulatory approvals for the treatment of selected patients with breast cancer, certain other solid tumours or particular haematological malignancies. However, given the prominence of PI3K signalling in cancer and the crucial role of this pathway in linking cancer growth with metabolism, these clinical results could arguably be improved upon. In this Review, we discuss past and present efforts to overcome the somewhat limited clinical efficacy of PI3Kα pathway inhibitors, including optimization of inhibitor specificity, patient selection and biomarkers across cancer types, with a focus on breast cancer, as well as identification and abrogation of signalling-related and metabolic mechanisms of resistance, and interventions to improve management of prohibitive adverse events. We highlight the advantages and limitations of laboratory-based model systems used to study the PI3K pathway, and propose technologies and experimental inquiries to guide the future clinical deployment of PI3K pathway inhibitors in the treatment of cancer.
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Neoplasias de la Mama , Fosfatidilinositol 3-Quinasa , Neoplasias de la Mama/tratamiento farmacológico , Carcinogénesis , Femenino , Humanos , Fosfatidilinositol 3-Quinasa/metabolismo , Fosfatidilinositol 3-Quinasas/genética , Fosfatidilinositol 3-Quinasas/metabolismo , Inhibidores de las Quinasa Fosfoinosítidos-3/uso terapéutico , Proteínas Proto-Oncogénicas c-aktRESUMEN
De novo metastatic breast cancer (dnMBC) represents a minority of MBC cases, and as such, its genomics are poorly understood. Characterizing the genomics of dnMBC represents an opportunity to delineate metastatic drivers in the absence of treatment selection. In this review, we first summarize the literature of the genomics of MBC which showed that MBCs have greater mutational burden than early stage, treatment naïve breast cancers. We then turn to recent studies that have sought to focus on dnMBC. We propose that understanding genomic differences between dnMBC and relapsed MBC can inform treatment choices. Finally, we discuss translational strategies to better dissect the genomics of dnMBC.
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Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Pruebas Genéticas , Mutación , Femenino , Genómica , Humanos , Metástasis de la Neoplasia , Recurrencia Local de Neoplasia/patología , PronósticoRESUMEN
Fructose consumption is linked to the rising incidence of obesity and cancer, which are two of the leading causes of morbidity and mortality globally1,2. Dietary fructose metabolism begins at the epithelium of the small intestine, where fructose is transported by glucose transporter type 5 (GLUT5; encoded by SLC2A5) and phosphorylated by ketohexokinase to form fructose 1-phosphate, which accumulates to high levels in the cell3,4. Although this pathway has been implicated in obesity and tumour promotion, the exact mechanism that drives these pathologies in the intestine remains unclear. Here we show that dietary fructose improves the survival of intestinal cells and increases intestinal villus length in several mouse models. The increase in villus length expands the surface area of the gut and increases nutrient absorption and adiposity in mice that are fed a high-fat diet. In hypoxic intestinal cells, fructose 1-phosphate inhibits the M2 isoform of pyruvate kinase to promote cell survival5-7. Genetic ablation of ketohexokinase or stimulation of pyruvate kinase prevents villus elongation and abolishes the nutrient absorption and tumour growth that are induced by feeding mice with high-fructose corn syrup. The ability of fructose to promote cell survival through an allosteric metabolite thus provides additional insights into the excess adiposity generated by a Western diet, and a compelling explanation for the promotion of tumour growth by high-fructose corn syrup.
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Fructosa/farmacología , Jarabe de Maíz Alto en Fructosa/farmacología , Absorción Intestinal/efectos de los fármacos , Mucosa Intestinal/citología , Mucosa Intestinal/efectos de los fármacos , Nutrientes/metabolismo , Animales , Supervivencia Celular/efectos de los fármacos , Activación Enzimática , Femenino , Fructoquinasas/metabolismo , Fructosa/metabolismo , Jarabe de Maíz Alto en Fructosa/metabolismo , Hipoxia/dietoterapia , Hipoxia/patología , Mucosa Intestinal/metabolismo , Metabolismo de los Lípidos/efectos de los fármacos , Masculino , Ratones , Piruvato Quinasa/metabolismoRESUMEN
Alpelisib is a α-selective phosphatidylinositol 3-kinase (PI3K) inhibitor approved for treatment of postmenopausal women, and men, with hormone receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2-), PIK3CA-mutated, advanced breast cancer (ABC). Hyperglycemia is a common, on-target adverse effect that impairs treatment efficacy and increases the rate of treatment delays, dose reductions, and discontinuation. Currently, there are no clear guidelines on how to manage hyperglycemia due to alpelisib when metformin is not effective. In this case series, we review 3 subjects with ABC that developed hyperglycemia during alpelisib-fulvestrant therapy and were successfully managed with dietary and pharmacologic interventions. These cases provide anecdotal evidence to support the use of sodium-glucose co-transporter-2 inhibitors (SGLT2i) and very low carbohydrate diets to minimize hyperglycemia during alpelisib therapy.
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Hiperglucemia , Inhibidores del Cotransportador de Sodio-Glucosa 2 , Simportadores , Dieta Baja en Carbohidratos , Femenino , Glucosa , Humanos , Hiperglucemia/inducido químicamente , Hiperglucemia/tratamiento farmacológico , Masculino , Fosfatidilinositol 3-Quinasas , Receptor ErbB-2/metabolismo , Sodio , TiazolesRESUMEN
On-target resistance to next-generation TRK inhibitors in TRK fusion-positive cancers is largely uncharacterized. In patients with these tumors, we found that TRK xDFG mutations confer resistance to type I next-generation TRK inhibitors designed to maintain potency against several kinase domain mutations. Computational modeling and biochemical assays showed that TRKAG667 and TRKCG696 xDFG substitutions reduce drug binding by generating steric hindrance. Concurrently, these mutations stabilize the inactive (DFG-out) conformations of the kinases, thus sensitizing these kinases to type II TRK inhibitors. Consistently, type II inhibitors impede the growth and TRK-mediated signaling of xDFG-mutant isogenic and patient-derived models. Collectively, these data demonstrate that adaptive conformational resistance can be abrogated by shifting kinase engagement modes. Given the prior identification of paralogous xDFG resistance mutations in other oncogene-addicted cancers, these findings provide insights into rational type II drug design by leveraging inhibitor class affinity switching to address recalcitrant resistant alterations. SIGNIFICANCE: In TRK fusion-positive cancers, TRK xDFG substitutions represent a shared liability for type I TRK inhibitors. In contrast, they represent a potential biomarker of type II TRK inhibitor activity. As all currently available type II agents are multikinase inhibitors, rational drug design should focus on selective type II inhibitor creation.This article is highlighted in the In This Issue feature, p. 1.
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Neoplasias , Receptor trkA , Humanos , Mutación , Neoplasias/tratamiento farmacológico , Neoplasias/genética , Oncogenes , Inhibidores de Proteínas Quinasas/farmacología , Receptor trkA/genéticaRESUMEN
Cytosolic DNA is characteristic of chromosomally unstable metastatic cancer cells, resulting in constitutive activation of the cGAS-STING innate immune pathway. How tumors co-opt inflammatory signaling while evading immune surveillance remains unknown. Here, we show that the ectonucleotidase ENPP1 promotes metastasis by selectively degrading extracellular cGAMP, an immune-stimulatory metabolite whose breakdown products include the immune suppressor adenosine. ENPP1 loss suppresses metastasis, restores tumor immune infiltration, and potentiates response to immune checkpoint blockade in a manner dependent on tumor cGAS and host STING. Conversely, overexpression of wild-type ENPP1, but not an enzymatically weakened mutant, promotes migration and metastasis, in part through the generation of extracellular adenosine, and renders otherwise sensitive tumors completely resistant to immunotherapy. In human cancers, ENPP1 expression correlates with reduced immune cell infiltration, increased metastasis, and resistance to anti-PD-1/PD-L1 treatment. Thus, cGAMP hydrolysis by ENPP1 enables chromosomally unstable tumors to transmute cGAS activation into an immune-suppressive pathway. SIGNIFICANCE: Chromosomal instability promotes metastasis by generating chronic tumor inflammation. ENPP1 facilitates metastasis and enables tumor cells to tolerate inflammation by hydrolyzing the immunotransmitter cGAMP, preventing its transfer from cancer cells to immune cells.This article is highlighted in the In This Issue feature, p. 995.
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Metástasis de la Neoplasia , Neoplasias/terapia , Nucleótidos Cíclicos/metabolismo , Escape del Tumor , Animales , Humanos , Hidrólisis , Inmunoterapia , Ratones , Ratones Endogámicos BALB C , Neoplasias/metabolismo , Neoplasias/patologíaRESUMEN
Alpelisib is a selective inhibitor of PI3Kα, shown to improve outcomes for PIK3CA mutant, hormone receptor positive (HR+) metastatic breast cancers (MBC) when combined with antiestrogen therapy. To uncover mechanisms of resistance, we conducted a detailed, longitudinal analysis of tumor and plasma circulating tumor DNA among such patients from a phase I/II trial combining alpelisib with an aromatase inhibitor (AI) (NCT01870505). The trial's primary objective was to establish safety with maculopapular rash emerging as the most common grade 3 adverse event (33%). Among 44 evaluable patients, the observed clinical benefit rate was 52%. Correlating genetic alterations with outcome, we identified loss-of-function PTEN mutations in 25% of patients with resistance. ESR1 activating mutations also expanded in number and allele fraction during treatment and were associated with resistance. These data indicate that genomic alterations that mediate resistance to alpelisib or antiestrogen may promote disease progression and highlight PTEN loss as a recurrent mechanism of resistance to PI3Kα inhibition.
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Inhibidores de la Aromatasa , Neoplasias de la Mama , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Inhibidores de la Aromatasa/farmacología , Neoplasias de la Mama/tratamiento farmacológico , Moduladores de los Receptores de Estrógeno/uso terapéutico , Femenino , Humanos , Fosfohidrolasa PTEN/genética , Receptor ErbB-2/genética , Receptores de Estrógenos/genética , TiazolesRESUMEN
Cancers develop as a result of driver mutations1,2 that lead to clonal outgrowth and the evolution of disease3,4. The discovery and functional characterization of individual driver mutations are central aims of cancer research, and have elucidated myriad phenotypes5 and therapeutic vulnerabilities6. However, the serial genetic evolution of mutant cancer genes7,8 and the allelic context in which they arise is poorly understood in both common and rare cancer genes and tumour types. Here we find that nearly one in four human tumours contains a composite mutation of a cancer-associated gene, defined as two or more nonsynonymous somatic mutations in the same gene and tumour. Composite mutations are enriched in specific genes, have an elevated rate of use of less-common hotspot mutations acquired in a chronology driven in part by oncogenic fitness, and arise in an allelic configuration that reflects context-specific selective pressures. cis-acting composite mutations are hypermorphic in some genes in which dosage effects predominate (such as TERT), whereas they lead to selection of function in other genes (such as TP53). Collectively, composite mutations are driver alterations that arise from context- and allele-specific selective pressures that are dependent in part on gene and mutation function, and which lead to complex-often neomorphic-functions of biological and therapeutic importance.
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Carcinogénesis/genética , Modelos Genéticos , Mutación , Neoplasias/genética , Oncogenes/genética , Alelos , Animales , Femenino , Genes p53/genética , Humanos , Ratones , Selección Genética , Telomerasa/genéticaRESUMEN
Activating mutations in PIK3CA are frequent in human breast cancer, and phosphoinositide 3-kinase alpha (PI3Kα) inhibitors have been approved for therapy. To characterize determinants of sensitivity to these agents, we analyzed PIK3CA-mutant cancer genomes and observed the presence of multiple PIK3CA mutations in 12 to 15% of breast cancers and other tumor types, most of which (95%) are double mutations. Double PIK3CA mutations are in cis on the same allele and result in increased PI3K activity, enhanced downstream signaling, increased cell proliferation, and tumor growth. The biochemical mechanisms of dual mutations include increased disruption of p110α binding to the inhibitory subunit p85α, which relieves its catalytic inhibition, and increased p110α membrane lipid binding. Double PIK3CA mutations predict increased sensitivity to PI3Kα inhibitors compared with single-hotspot mutations.