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PURPOSE: Resistance to endocrine therapy (ET) and CDK4/6 inhibitors (CDK4/6i) is a clinical challenge in estrogen receptor (ER)-positive (ER+) breast cancer. Cyclin-dependent kinase 7 (CDK7) is a candidate target in endocrine-resistant ER+ breast cancer models and selective CDK7 inhibitors (CDK7i) are in clinical development for the treatment of ER+ breast cancer. Nonetheless, the precise mechanisms responsible for the activity of CDK7i in ER+ breast cancer remain elusive. Herein, we sought to unravel these mechanisms. EXPERIMENTAL DESIGN: We conducted multi-omic analyses in ER+ breast cancer models in vitro and in vivo, including models with different genetic backgrounds. We also performed genome-wide CRISPR/Cas9 knockout screens to identify potential therapeutic vulnerabilities in CDK4/6i-resistant models. RESULTS: We found that the on-target antitumor effects of CDK7 inhibition in ER+ breast cancer are in part p53 dependent, and involve cell cycle inhibition and suppression of c-Myc. Moreover, CDK7 inhibition exhibited cytotoxic effects, distinctive from the cytostatic nature of ET and CDK4/6i. CDK7 inhibition resulted in suppression of ER phosphorylation at S118; however, long-term CDK7 inhibition resulted in increased ER signaling, supporting the combination of ET with a CDK7i. Finally, genome-wide CRISPR/Cas9 knockout screens identified CDK7 and MYC signaling as putative vulnerabilities in CDK4/6i resistance, and CDK7 inhibition effectively inhibited CDK4/6i-resistant models. CONCLUSIONS: Taken together, these findings support the clinical investigation of selective CDK7 inhibition combined with ET to overcome treatment resistance in ER+ breast cancer. In addition, our study highlights the potential of increased c-Myc activity and intact p53 as predictors of sensitivity to CDK7i-based treatments.
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Apoptosis , Neoplasias de la Mama , Ciclo Celular , Quinasa Activadora de Quinasas Ciclina-Dependientes , Quinasas Ciclina-Dependientes , Resistencia a Antineoplásicos , Inhibidores de Proteínas Quinasas , Proteínas Proto-Oncogénicas c-myc , Receptores de Estrógenos , Transducción de Señal , Humanos , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Neoplasias de la Mama/genética , Neoplasias de la Mama/metabolismo , Femenino , Resistencia a Antineoplásicos/genética , Apoptosis/efectos de los fármacos , Animales , Ratones , Receptores de Estrógenos/metabolismo , Quinasas Ciclina-Dependientes/antagonistas & inhibidores , Quinasas Ciclina-Dependientes/metabolismo , Quinasas Ciclina-Dependientes/genética , Proteínas Proto-Oncogénicas c-myc/metabolismo , Proteínas Proto-Oncogénicas c-myc/genética , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico , Transducción de Señal/efectos de los fármacos , Ciclo Celular/efectos de los fármacos , Ensayos Antitumor por Modelo de Xenoinjerto , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Quinasa 4 Dependiente de la Ciclina/antagonistas & inhibidores , Quinasa 4 Dependiente de la Ciclina/genética , Sistemas CRISPR-CasRESUMEN
ABSTRACT: Acute myeloid leukemia (AML) is an aggressive hematological malignancy originating from transformed hematopoietic stem or progenitor cells. AML prognosis remains poor owing to resistance and relapse driven by leukemia stem cells (LSCs). Targeting molecules essential for LSC function is a promising therapeutic approach. The phosphatidylinositol 3-kinase (PI3K)/AKT pathway is often dysregulated in AML. We found that although PI3Kγ is highly enriched in LSCs and critical for self-renewal, it was dispensable for normal hematopoietic stem cells. Mechanistically, PI3Kγ-AKT signaling promotes nuclear factor erythroid 2-related factor 2 (NRF2) nuclear accumulation, which induces 6-phosphogluconate dehydrogenase (PGD) and the pentose phosphate pathway, thereby maintaining LSC stemness. Importantly, genetic or pharmacological inhibition of PI3Kγ impaired expansion and stemness of murine and human AML cells in vitro and in vivo. Together, our findings reveal a key role for PI3Kγ in selectively maintaining LSC function by regulating AKT-NRF2-PGD metabolic pathway. Targeting the PI3Kγ pathway may, therefore, eliminate LSCs without damaging normal hematopoiesis, providing a promising therapeutic strategy for AML.
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Fosfatidilinositol 3-Quinasa Clase Ib , Leucemia Mieloide Aguda , Células Madre Neoplásicas , Vía de Pentosa Fosfato , Animales , Humanos , Ratones , Autorrenovación de las Células , Fosfatidilinositol 3-Quinasa Clase Ib/metabolismo , Fosfatidilinositol 3-Quinasa Clase Ib/genética , Leucemia Mieloide Aguda/patología , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/genética , Células Madre Neoplásicas/metabolismo , Células Madre Neoplásicas/patología , Factor 2 Relacionado con NF-E2/metabolismo , Factor 2 Relacionado con NF-E2/genética , Vía de Pentosa Fosfato/genética , Proteínas Proto-Oncogénicas c-akt/metabolismo , Proteínas Proto-Oncogénicas c-akt/genética , Transducción de SeñalRESUMEN
Vitamin C (vitC) is a vital nutrient for health and also used as a therapeutic agent in diseases such as cancer. However, the mechanisms underlying vitC's effects remain elusive. Here we report that vitC directly modifies lysine without enzymes to form vitcyl-lysine, termed "vitcylation", in a dose-, pH-, and sequence-dependent manner across diverse proteins in cells. We further discover that vitC vitcylates K298 site of STAT1, which impairs its interaction with the phosphatase PTPN2, preventing STAT1 Y701 dephosphorylation and leading to increased STAT1-mediated IFN pathway activation in tumor cells. As a result, these cells have increased MHC/HLA class-I expression and activate immune cells in co-cultures. Tumors collected from vitC-treated tumor-bearing mice have enhanced vitcylation, STAT1 phosphorylation and antigen presentation. The identification of vitcylation as a novel PTM and the characterization of its effect in tumor cells opens a new avenue for understanding vitC in cellular processes, disease mechanisms, and therapeutics.
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Loss of the PTEN tumour suppressor is one of the most common oncogenic drivers across all cancer types1. PTEN is the major negative regulator of PI3K signalling. The PI3Kß isoform has been shown to play an important role in PTEN-deficient tumours, but the mechanisms underlying the importance of PI3Kß activity remain elusive. Here, using a syngeneic genetically engineered mouse model of invasive breast cancer driven by ablation of both Pten and Trp53 (which encodes p53), we show that genetic inactivation of PI3Kß led to a robust anti-tumour immune response that abrogated tumour growth in syngeneic immunocompetent mice, but not in immunodeficient mice. Mechanistically, PI3Kß inactivation in the PTEN-null setting led to reduced STAT3 signalling and increased the expression of immune stimulatory molecules, thereby promoting anti-tumour immune responses. Pharmacological PI3Kß inhibition also elicited anti-tumour immunity and synergized with immunotherapy to inhibit tumour growth. Mice with complete responses to the combined treatment displayed immune memory and rejected tumours upon re-challenge. Our findings demonstrate a molecular mechanism linking PTEN loss and STAT3 activation in cancer and suggest that PI3Kß controls immune escape in PTEN-null tumours, providing a rationale for combining PI3Kß inhibitors with immunotherapy for the treatment of PTEN-deficient breast cancer.
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Evasión Inmune , Neoplasias Mamarias Animales , Fosfohidrolasa PTEN , Fosfatidilinositol 3-Quinasa , Animales , Ratones , Inmunoterapia , Fosfatidilinositol 3-Quinasa/metabolismo , Inhibidores de las Quinasa Fosfoinosítidos-3 , Fosfohidrolasa PTEN/deficiencia , Fosfohidrolasa PTEN/genética , Transducción de Señal , Neoplasias Mamarias Animales/enzimología , Neoplasias Mamarias Animales/genética , Neoplasias Mamarias Animales/inmunología , Neoplasias Mamarias Experimentales/enzimología , Neoplasias Mamarias Experimentales/genética , Neoplasias Mamarias Experimentales/inmunologíaRESUMEN
Lactate is abundant in rapidly dividing cells owing to the requirement for elevated glucose catabolism to support proliferation1-6. However, it is not known whether accumulated lactate affects the proliferative state. Here we use a systematic approach to determine lactate-dependent regulation of proteins across the human proteome. From these data, we identify a mechanism of cell cycle regulation whereby accumulated lactate remodels the anaphase promoting complex (APC/C). Remodelling of APC/C in this way is caused by direct inhibition of the SUMO protease SENP1 by lactate. We find that accumulated lactate binds and inhibits SENP1 by forming a complex with zinc in the SENP1 active site. SENP1 inhibition by lactate stabilizes SUMOylation of two residues on APC4, which drives UBE2C binding to APC/C. This direct regulation of APC/C by lactate stimulates timed degradation of cell cycle proteins, and efficient mitotic exit in proliferative human cells. This mechanism is initiated upon mitotic entry when lactate abundance reaches its apex. In this way, accumulation of lactate communicates the consequences of a nutrient-replete growth phase to stimulate timed opening of APC/C, cell division and proliferation. Conversely, persistent accumulation of lactate drives aberrant APC/C remodelling and can overcome anti-mitotic pharmacology via mitotic slippage. In sum, we define a biochemical mechanism through which lactate directly regulates protein function to control the cell cycle and proliferation.
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Ciclosoma-Complejo Promotor de la Anafase , Proteínas de Ciclo Celular , Ciclo Celular , Ácido Láctico , Humanos , Anafase , Ciclosoma-Complejo Promotor de la Anafase/metabolismo , Proteínas de Ciclo Celular/metabolismo , Ácido Láctico/metabolismo , MitosisRESUMEN
Introduction: Despite the impressive clinical response rate of osimertinib, a third-generation EGFR-TKI, as a frontline treatment for patients with EGFR-mutant non-small-cell lung cancer (NSCLC) or as a salvage therapy for patients with T790M mutation, resistance to osimertinib is common in the clinic. The mechanisms underlying osimertinib resistance are heterogenous. While genetic mutations within EGFR or other cancer driver pathways mediated mechanisms are well-documented, the role of tumor cell and tumor immune microenvironment in mediating the response to osimertinib remains elusive. Methods and results: Here, using a syngeneic mouse model of EGFR-mutant lung cancer, we show that tumor regression elicited by osimertinib requires activation of CD8+ T cells. However, tumor-associated macrophages (TAMs) accumulated in advanced tumors inhibit CD8+ T cell activation and diminish the response to osimertinib. These results are corroborated by analyses of clinical data. Notably, reprogramming TAMs with a systemic STING agonist MSA-2 reinvigorates antitumor immunity and leads to durable tumor regression in mice when combined with osimertinib. Discussion: Our results reveal a new mechanism of EGFR-TKI resistance and suggest a new therapeutic strategy for the treatment of EGFR-mutant tumors.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Animales , Ratones , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Línea Celular Tumoral , Resistencia a Antineoplásicos/genética , Receptores ErbB/metabolismo , Neoplasias Pulmonares/patología , Mutación , Inhibidores de Proteínas Quinasas/farmacología , Microambiente Tumoral , Macrófagos Asociados a Tumores/metabolismoRESUMEN
3'-Phosphoinositides are ubiquitous cellular lipids that play pivotal regulatory roles in health and disease. Generation of 3'-phosphoinositides are driven by three families of phosphoinositide 3-kinases (PI3K) but the mechanisms underlying their regulation and cross-talk are not fully understood. Among 3'-phosphoinositides, phosphatidylinositol-3,5-bisphosphate (PI(3,5)P 2 ) remains the least understood species in terms of its spatiotemporal dynamics and physiological function due to the lack of specific probes. By means of spatiotemporally resolved in situ quantitative imaging of PI(3,5)P 2 using a newly developed ratiometric PI(3,5)P 2 sensor we demonstrate that a special pool of PI(3,5)P 2 is generated on lysosomes and late endosomes in response to growth factor stimulation. This PI(3,5)P 2 pool, the formation of which is mediated by Class II PI3KC2ß and PIKFyve, plays a crucial role in terminating the activity of growth factor-stimulated Class I PI3K, one of the most frequently mutated proteins in cancer, via specific interaction with its regulatory p85 subunit. Cancer-causing mutations of Class I PI3K inhibit the p85-PI(3,5)P 2 interaction and thereby induce sustained activation of Class I PI3K. Our results unravel a hitherto unknown tight regulatory interplay between Class I and II PI3Ks mediated by PI(3,5)P 2 , which may be important for controlling the strength of PI3K-mediated growth factor signaling. These results also suggest a new therapeutic possibility of treating cancer patients with p85 mutations.
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BACKGROUND: Poly (ADP-ribose) polymerase (PARP) inhibition (PARPi) has demonstrated potent therapeutic efficacy in patients with BRCA-mutant ovarian cancer. However, acquired resistance to PARPi remains a major challenge in the clinic. METHODS: PARPi-resistant ovarian cancer mouse models were generated by long-term treatment of olaparib in syngeneic Brca1-deficient ovarian tumors. Signal transducer and activator of transcription 3 (STAT3)-mediated immunosuppression was investigated in vitro by co-culture experiments and in vivo by analysis of immune cells in the tumor microenvironment (TME) of human and mouse PARPi-resistant tumors. Whole genome transcriptome analysis was performed to assess the antitumor immunomodulatory effect of STING (stimulator of interferon genes) agonists on myeloid cells in the TME of PARPi-resistant ovarian tumors. A STING agonist was used to overcome STAT3-mediated immunosuppression and acquired PARPi resistance in syngeneic and patient-derived xenografts models of ovarian cancer. RESULTS: In this study, we uncover an adaptive resistance mechanism to PARP inhibition mediated by tumor-associated macrophages (TAMs) in the TME. Markedly increased populations of protumor macrophages are found in BRCA-deficient ovarian tumors that rendered resistance to PARPi in both murine models and patients. Mechanistically, PARP inhibition elevates the STAT3 signaling pathway in tumor cells, which in turn promotes protumor polarization of TAMs. STAT3 ablation in tumor cells mitigates polarization of protumor macrophages and increases tumor-infiltrating T cells on PARP inhibition. These findings are corroborated in patient-derived, PARPi-resistant BRCA1-mutant ovarian tumors. Importantly, STING agonists reshape the immunosuppressive TME by reprogramming myeloid cells and overcome the TME-dependent adaptive resistance to PARPi in ovarian cancer. This effect is further enhanced by addition of the programmed cell death protein-1 blockade. CONCLUSIONS: We elucidate an adaptive immunosuppression mechanism rendering resistance to PARPi in BRCA1-mutant ovarian tumors. This is mediated by enrichment of protumor TAMs propelled by PARPi-induced STAT3 activation in tumor cells. We also provide a new strategy to reshape the immunosuppressive TME with STING agonists and overcome PARPi resistance in ovarian cancer.
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Neoplasias Ováricas , Inhibidores de Poli(ADP-Ribosa) Polimerasas , Animales , Femenino , Humanos , Ratones , Línea Celular Tumoral , Terapia de Inmunosupresión , Neoplasias Ováricas/genética , Inhibidores de Poli(ADP-Ribosa) Polimerasas/farmacología , Factor de Transcripción STAT3/metabolismo , Microambiente TumoralRESUMEN
PURPOSE: Brain metastases can occur in up to 50% of patients with metastatic HER2-positive breast cancer. Because patients with active brain metastases were excluded from previous pivotal clinical trials, the central nervous system (CNS) activity of the antibody-drug conjugate trastuzumab deruxtecan (T-DXd) is not well characterized. EXPERIMENTAL DESIGN: We studied how T-DXd affects growth and overall survival in orthotopic patient-derived xenografts (PDX) of HER2-positive and HER2-low breast cancer brain metastases (BCBM). Separately, we evaluated the effects of T-DXd in a retrospective cohort study of 17 patients with stable or active brain metastases. RESULTS: T-DXd inhibited tumor growth and prolonged survival in orthotopic PDX models of HER2-positive (IHC 3+) and HER2-low (IHC 2+/FISH ratio < 2) BCBMs. T-DXd reduced tumor size and prolonged survival in a T-DM1-resistant HER2-positive BCBM PDX model. In a retrospective multi-institutional cohort study of 17 patients with predominantly HER2-positive BCBMs, the CNS objective response rate (ORR) was 73% (11/15) while extracranial response rate was 45% (5/11). In the subset of patients with untreated or progressive BCBM at baseline, the CNS ORR was 70% (7/10). The median time on treatment with T-DXd was 8.9 (1.3-16.2) months, with 42% (7/17) remaining on treatment at data cutoff. CONCLUSIONS: T-DXd demonstrates evidence of CNS activity in HER2-positive and HER2-low PDX models of BCBM and preliminary evidence of clinical efficacy in a multi-institution case series of patients with BCBM. Prospective clinical trials to further evaluate CNS activity of T-DXd in patients with active brain metastases are warranted. See related commentary by Soffietti and Pellerino, p. 8.
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Neoplasias Encefálicas , Neoplasias de la Mama , Inmunoconjugados , Humanos , Femenino , Estudios Retrospectivos , Estudios de Cohortes , Estudios Prospectivos , Receptor ErbB-2/uso terapéutico , Trastuzumab/efectos adversos , Neoplasias de la Mama/patología , Camptotecina/uso terapéutico , Inmunoconjugados/uso terapéutico , Neoplasias Encefálicas/mortalidad , Resultado del TratamientoRESUMEN
The mutant form of the guanosine triphosphatase (GTPase) KRAS is a key driver in human tumors but remains a challenging therapeutic target, making KRASMUT cancers a highly unmet clinical need. Here, we report a class of bottlebrush polyethylene glycol (PEG)-conjugated antisense oligonucleotides (ASOs) for potent in vivo KRAS depletion. Owing to their highly branched architecture, these molecular nanoconstructs suppress nearly all side effects associated with DNA-protein interactions and substantially enhance the pharmacological properties of the ASO, such as plasma pharmacokinetics and tumor uptake. Systemic delivery to mice bearing human non-small-cell lung carcinoma xenografts results in a significant reduction in both KRAS levels and tumor growth, and the antitumor performance well exceeds that of current popular ASO paradigms, such as chemically modified oligonucleotides and PEGylation using linear or slightly branched PEG. Importantly, these conjugates relax the requirement on the ASO chemistry, allowing unmodified, natural phosphodiester ASOs to achieve efficacy comparable to that of chemically modified ones. Both the bottlebrush polymer and its ASO conjugates appear to be safe and well tolerated in mice. Together, these data indicate that the molecular brush-ASO conjugate is a promising therapeutic platform for the treatment of KRAS-driven human cancers and warrant further preclinical and clinical development.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Terapia Molecular Dirigida , Oligonucleótidos Antisentido , Proteínas Proto-Oncogénicas p21(ras) , Animales , Carcinoma de Pulmón de Células no Pequeñas/terapia , Humanos , Neoplasias Pulmonares/terapia , Ratones , Oligonucleótidos Antisentido/química , Oligonucleótidos Antisentido/uso terapéutico , Polietilenglicoles , Proteínas Proto-Oncogénicas p21(ras)/antagonistas & inhibidores , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
PARP inhibitors (PARPi) have drastically changed the treatment landscape of advanced ovarian tumors with BRCA mutations. However, the impact of this class of inhibitors in patients with advanced BRCA-mutant breast cancer is relatively modest. Using a syngeneic genetically-engineered mouse model of breast tumor driven by Brca1 deficiency, we show that tumor-associated macrophages (TAMs) blunt PARPi efficacy both in vivo and in vitro. Mechanistically, BRCA1-deficient breast tumor cells induce pro-tumor polarization of TAMs, which in turn suppress PARPi-elicited DNA damage in tumor cells, leading to reduced production of dsDNA fragments and synthetic lethality, hence impairing STING-dependent anti-tumor immunity. STING agonists reprogram M2-like pro-tumor macrophages into an M1-like anti-tumor state in a macrophage STING-dependent manner. Systemic administration of a STING agonist breaches multiple layers of tumor cell-mediated suppression of immune cells, and synergizes with PARPi to suppress tumor growth. The therapeutic benefits of this combination require host STING and are mediated by a type I IFN response and CD8+ T cells, but do not rely on tumor cell-intrinsic STING. Our data illustrate the importance of targeting innate immune suppression to facilitate PARPi-mediated engagement of anti-tumor immunity in breast cancer.
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Neoplasias de la Mama , Inhibidores de Poli(ADP-Ribosa) Polimerasas , Animales , Proteína BRCA1/genética , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/genética , Linfocitos T CD8-positivos , Femenino , Humanos , Ratones , Inhibidores de Poli(ADP-Ribosa) Polimerasas/farmacología , Inhibidores de Poli(ADP-Ribosa) Polimerasas/uso terapéutico , Mutaciones Letales Sintéticas , Macrófagos Asociados a TumoresRESUMEN
Nucleic-acid-based immune adjuvants have been extensively investigated for the design of cancer vaccines. However, nucleic acids often require the assistance of a carrier system to improve cellular uptake. Yet, such systems are prone to carrier-associated adaptive immunity, leading to difficulties in a multidose treatment regimen. Here, we demonstrate that a spherical nucleic acid (SNA)-based self-adjuvanting system consisting of phosphodiester oligonucleotides and vitamin E can function as a potent anticancer vaccine without a carrier. The two functional modules work synergistically, serving as each other's delivery vector to enhance toll-like receptor 9 activation. The vaccine rapidly enters cells carrying OVA model antigens, which enables efficient activation of adaptive immunity in vitro and in vivo. In OVA-expressing tumor allograft models, both prophylactic and therapeutic vaccinations significantly retard tumor growth and prolong animal survival. Furthermore, the vaccinations were also able to reduce lung metastasis in a B16F10-OVA model.
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Vacunas contra el Cáncer , Inmunoterapia , Neoplasias , Ácidos Nucleicos , Receptor Toll-Like 9 , Adyuvantes Inmunológicos/uso terapéutico , Animales , Inmunoterapia/métodos , Ratones , Ratones Endogámicos C57BL , Neoplasias/tratamiento farmacológico , Ácidos Nucleicos/uso terapéutico , Receptor Toll-Like 9/genética , Receptor Toll-Like 9/uso terapéuticoRESUMEN
Protein fatty acylation regulates numerous cell signaling pathways. Polyunsaturated fatty acids (PUFAs) exert a plethora of physiological effects, including cell signaling regulation, with underlying mechanisms to be fully understood. Herein, we report that docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) regulate PI3K-AKT signaling by modifying PDK1 and AKT2. DHA-administered mice exhibit altered phosphorylation of proteins in signaling pathways. Methylene bridge-containing DHA/EPA acylate δ1 carbon of tryptophan 448/543 in PDK1 and tryptophan 414 in AKT2 via free radical pathway, recruit both the proteins to the cytoplasmic membrane, and activate PI3K signaling and glucose uptake in a tryptophan acylation-dependent but insulin-independent manner in cultured cells and in mice. DHA/EPA deplete cytosolic PDK1 and AKT2 and induce insulin resistance. Akt2 knockout in mice abrogates DHA/EPA-induced PI3K-AKT signaling. Our results identify PUFA's methylene bridge tryptophan acylation, a protein fatty acylation that regulates cell signaling and may underlie multifaceted effects of methylene-bridge-containing PUFAs.
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Fosfatidilinositol 3-Quinasas , Triptófano , Acilación , Animales , Ácidos Docosahexaenoicos/metabolismo , Ácidos Docosahexaenoicos/farmacología , Ácido Eicosapentaenoico/metabolismo , Ácido Eicosapentaenoico/farmacología , Ácidos Grasos Insaturados , Glucosa/metabolismo , Ratones , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Transducción de Señal , Triptófano/metabolismoRESUMEN
Approximately 50% of patients with metastatic HER2-positive (HER2+) breast cancer develop brain metastases (BCBMs). We report that the tumor suppressor p16INK4A is deficient in the majority of HER2+ BCBMs. p16INK4A-deficiency as measured by protein immunohistochemistry predicted response to combined tucatinib and abemaciclib in orthotopic patient-derived xenografts (PDXs) of HER2 + BCBMs. Our findings establish the rationale for a biomarker-driven clinical trial of combined CDK4/6- and HER2-targeted agents for patients with HER2 + BCBM.
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Antineoplásicos , Neoplasias Encefálicas , Neoplasias de la Mama , Antineoplásicos/uso terapéutico , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patología , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/genética , Neoplasias de la Mama/metabolismo , Quinasa 4 Dependiente de la Ciclina , Inhibidor p16 de la Quinasa Dependiente de Ciclina/genética , Femenino , Humanos , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismoRESUMEN
Cyclin-dependent kinase 4 (CDK4) and CDK6 are critical mediators of cellular transition into S phase and are important for the initiation, growth and survival of many cancer types. Pharmacological inhibitors of CDK4/6 have rapidly become a new standard of care for patients with advanced hormone receptor-positive breast cancer. As expected, CDK4/6 inhibitors arrest sensitive tumour cells in the G1 phase of the cell cycle. However, the effects of CDK4/6 inhibition are far more wide-reaching. New insights into their mechanisms of action have triggered identification of new therapeutic opportunities, including the development of novel combination regimens, expanded application to a broader range of cancers and use as supportive care to ameliorate the toxic effects of other therapies. Exploring these new opportunities in the clinic is an urgent priority, which in many cases has not been adequately addressed. Here, we provide a framework for conceptualizing the activity of CDK4/6 inhibitors in cancer and explain how this framework might shape the future clinical development of these agents. We also discuss the biological underpinnings of CDK4/6 inhibitor resistance, an increasingly common challenge in clinical oncology.
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Neoplasias de la Mama , Inhibidores de Proteínas Quinasas , Neoplasias de la Mama/metabolismo , Ciclo Celular , Quinasa 4 Dependiente de la Ciclina , Quinasa 6 Dependiente de la Ciclina , Femenino , Humanos , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéuticoRESUMEN
Proliferation is a fundamental trait of cancer cells, but its properties and spatial organization in tumours are poorly characterized. Here we use highly multiplexed tissue imaging to perform single-cell quantification of cell cycle regulators and then develop robust, multivariate, proliferation metrics. Across diverse cancers, proliferative architecture is organized at two spatial scales: large domains, and smaller niches enriched for specific immune lineages. Some tumour cells express cell cycle regulators in the (canonical) patterns expected of freely growing cells, a phenomenon we refer to as 'cell cycle coherence'. By contrast, the cell cycles of other tumour cell populations are skewed towards specific phases or exhibit non-canonical (incoherent) marker combinations. Coherence varies across space, with changes in oncogene activity and therapeutic intervention, and is associated with aggressive tumour behaviour. Thus, multivariate measures from high-plex tissue images capture clinically significant features of cancer proliferation, a fundamental step in enabling more precise use of anti-cancer therapies.
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Neoplasias , Ciclo Celular , Proliferación Celular , Humanos , Neoplasias/genéticaRESUMEN
A common outcome of androgen deprivation in prostate cancer therapy is disease relapse and progression to castration-resistant prostate cancer (CRPC) via multiple mechanisms. To gain insight into the recent clinical findings that highlighted genomic alterations leading to hyperactivation of PI3K, we examined the roles of the commonly expressed p110 catalytic isoforms of PI3K in a murine model of Pten-null invasive CRPC. While blocking p110α had negligible effects in the development of Pten-null invasive CRPC, either genetic or pharmacologic perturbation of p110ß dramatically slowed CRPC initiation and progression. Once fully established, CRPC tumors became partially resistant to p110ß inhibition, indicating the acquisition of new dependencies. Driven by our genomic analyses highlighting potential roles for the p110ß/RAC/PAK1 and ß-catenin pathways in CRPC, we found that combining p110ß with RAC/PAK1 or tankyrase inhibitors significantly reduced the growth of murine and human CRPC organoids in vitro and in vivo. Because p110ß activity is dispensable for most physiologic processes, our studies support novel therapeutic strategies both for preventing disease progression into CRPC and for treating CRPC. IMPLICATIONS: This work establishes p110ß as a promising target for preventing the progression of primary PTEN-deficient prostate tumors to CRPC, and for treating established CRPC in combination with RAC/PAK1 or tankyrase inhibitors.
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Neoplasias de la Próstata Resistentes a la Castración , Tanquirasas , Antagonistas de Andrógenos , Animales , Humanos , Masculino , Ratones , Fosfohidrolasa PTEN/genética , Fosfatidilinositol 3-Quinasas , Próstata , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Neoplasias de la Próstata Resistentes a la Castración/genéticaRESUMEN
Cancer patients frequently develop chemotherapy-induced peripheral neuropathy (CIPN), a painful and long-lasting disorder with profound somatosensory deficits. There are no effective therapies to prevent or treat this disorder. Pathologically, CIPN is characterized by a "dying-back" axonopathy that begins at intra-epidermal nerve terminals of sensory neurons and progresses in a retrograde fashion. Calcium dysregulation constitutes a critical event in CIPN, but it is not known how chemotherapies such as paclitaxel alter intra-axonal calcium and cause degeneration. Here, we demonstrate that paclitaxel triggers Sarm1-dependent cADPR production in distal axons, promoting intra-axonal calcium flux from both intracellular and extracellular calcium stores. Genetic or pharmacologic antagonists of cADPR signaling prevent paclitaxel-induced axon degeneration and allodynia symptoms, without mitigating the anti-neoplastic efficacy of paclitaxel. Our data demonstrate that cADPR is a calcium-modulating factor that promotes paclitaxel-induced axon degeneration and suggest that targeting cADPR signaling provides a potential therapeutic approach for treating paclitaxel-induced peripheral neuropathy (PIPN).