The Role of Autophagy in Cancer Santana-Codina, Naiara; Mancias, Joseph D; Kimmelman, Alec C
Annual review of cancer biology,
03/2017, Letnik:
1, Številka:
1
Journal Article
Recenzirano
Odprti dostop
Autophagy is a highly conserved and regulated process that targets proteins and damaged organelles for lysosomal degradation to maintain cell metabolism, genomic integrity, and cell survival. The ...role of autophagy in cancer is dynamic and depends, in part, on tumor type and stage. Although autophagy constrains tumor initiation in normal tissue, some tumors rely on autophagy for tumor promotion and maintenance. Studies in genetically engineered mouse models support the idea that autophagy can constrain tumor initiation by regulating DNA damage and oxidative stress. In established tumors, autophagy can also be required for tumor maintenance, allowing tumors to survive environmental stress and providing intermediates for cell metabolism. Autophagy can also be induced in response to chemotherapeutics, acting as a drug-resistance mechanism. Therefore, targeting autophagy is an attractive cancer therapeutic option currently undergoing validation in clinical trials.
Immunotherapy has improved the clinical outcomes of patients with advanced non-small cell lung cancer (NSCLC). However, in patients with Kirsten rat sarcoma viral oncogene homolog (
) mutations, the ...superior efficacy of immunotherapy has not been elucidated and especially in real-world practice. Our study aimed to use real-world data to assess the efficacy of immunotherapy in
-mutant NSCLC in a Chinese cohort.
In this retrospective cohort study, we extracted the clinical, molecular, and pathologic data from the electronic health records of patients with advanced
-mutant NSCLC at Shandong Cancer Hospital between January 2018 and May 2022. Furthermore, we evaluated the progression-free survival (PFS) and overall survival (OS) of the included patients.
Between January 2018 and November 2020, 793 patients were identified with stage IIIB-IV NSCLC and a total of 122 patients with
mutations were included in the analysis. The majority of patients were diagnosed with stage IV (82.0%) adenocarcinoma (93.4%), along with a history of smoking (57.4%). Of these, 42% of patients received anti-PD-(L)1 with or without chemotherapy (Immunotherapy-based regimens), while 58.2% of patients received chemotherapy (Chemotherapy-based regimens). The median overall survival (mOS) in this cohort was 22.9 months (95% CI: 14.1-31.7), while the median-progression-free survival (mPFS) was 9.4 months (95% CI: 6.6-12.1). Patients receiving immunotherapy-based regimens displayed better mOS than those receiving chemotherapy-based regimens (45.2 vs. 11.3 months;
=1.81E-05), with no statistical difference observed in the mPFS (10.5 vs. 8.2 months;
=0.706). Patients receiving immunotherapy-based regimens either in the first line (
=0.00038,
=0.010, respectively) or second-line setting (
=0.010,
=0.026, respectively) showed benefits in both PFS and OS. Subgroup analysis indicated that in patients having
G12C or non-
G12C mutant types, immunotherapy showed benefits of better OS (
=0.0037,
=0.020, respectively) than chemotherapy. Moreover, in advanced NSCLCs patients with or without
co-mutation the immunotherapy-based regimen achieved longer OS and PFS than chemotherapy-based regimens.
In the Chinese population of patients with
-mutant advanced NSCLC, immunotherapy-based regimens achieved longer OS than chemotherapy-based regimens, which was independent of first or second-line setting, as well as
mutational subtypes.
KRAS plays a crucial role in regulating cell survival and proliferation and is one of the most commonly mutated oncogenes in human cancers. The novel KRASG12D inhibitor, MRTX1133, demonstrates ...promising antitumor efficacy in vitro and in vivo. However, the development of acquired resistance in treated patients presents a considerable challenge to sustained therapeutic effectiveness. In response to this challenge, we conducted site-specific mutagenesis screening to identify potential secondary mutations that could induce resistance to MRTX1133. We screened a range of KRASG12D variants harboring potential secondary mutations, and 44 representative variants were selected for in-depth validation of the pooled screening outcomes. We identified eight variants (G12D with V9E, V9W, V9Q, G13P, T58Y, R68G, Y96W, and Q99L) that exhibited substantial resistance, with V9W showing notable resistance, and downstream signaling analyses and structural modeling were conducted. We observed that secondary mutations in KRASG12D can lead to acquired resistance to MRTX1133 and BI-2865, a novel pan-KRAS inhibitor, in human cancer cell lines. This evidence is critical for devising new strategies to counteract resistance mechanisms and, ultimately, enhance treatment outcomes in patients with KRASG12D-mutant cancers.
•Secondary mutation in KRASG12D induces resistance to MRTX1133.•Site-specific mutagenesis screening identifies resistance-conferring variants.•The V9W mutation in KRASG12D shows significant resistance.•Downstream signaling analyses and structural modeling were utilized.•These insights aid in devising strategies against acquired resistance.
RAS genes are the most commonly mutated in human cancers and play critical roles in tumor initiation, progression, and drug resistance. Identification of targets that block RAS signaling is pivotal ...to develop therapies for RAS-related cancer. As RAS translocation to the plasma membrane (PM) is essential for its effective signal transduction, we devised a high-content screening assay to search for genes regulating KRAS membrane association. We found that the tyrosine phosphatase PTPN2 regulates the plasma membrane localization of KRAS. Knockdown of PTPN2 reduced the proliferation and promoted apoptosis in KRAS-dependent cancer cells, but not in KRAS-independent cells. Mechanistically, PTPN2 negatively regulates tyrosine phosphorylation of KRAS, which, in turn, affects the activation KRAS and its downstream signaling. Consistently, analysis of the TCGA database demonstrates that high expression of PTPN2 is significantly associated with poor prognosis of patients with KRAS-mutant pancreatic adenocarcinoma. These results indicate that PTPN2 is a key regulator of KRAS and may serve as a new target for therapy of KRAS-driven cancer.
Kirsten rat sarcoma 2 viral oncogene homolog (KRAS) is the most frequently mutated oncogene in human cancers with mutations predominantly occurring in codon 12. These mutations disrupt the normal ...function of KRAS by interfering with GTP hydrolysis and nucleotide exchange activity, making it prone to the GTP-bound active state, thus leading to sustained activation of downstream pathways. Despite decades of research, there has been no progress in the KRAS drug discovery until the groundbreaking discovery of covalently targeting the KRAS
mutation in 2013, which led to revolutionary changes in KRAS-targeted therapy. So far, two small molecule inhibitors sotorasib and adagrasib targeting KRAS
have received accelerated approval for the treatment of non-small cell lung cancer (NSCLC) harboring KRAS
mutations. In recent years, rapid progress has been achieved in the KRAS-targeted therapy field, especially the exploration of KRAS
covalent inhibitors in other KRAS
-positive malignancies, novel KRAS inhibitors beyond KRAS
mutation or pan-KRAS inhibitors, and approaches to indirectly targeting KRAS. In this review, we provide a comprehensive overview of the molecular and mutational characteristics of KRAS and summarize the development and current status of covalent inhibitors targeting the KRAS
mutation. We also discuss emerging promising KRAS-targeted therapeutic strategies, with a focus on mutation-specific and direct pan-KRAS inhibitors and indirect KRAS inhibitors through targeting the RAS activation-associated proteins Src homology-2 domain-containing phosphatase 2 (SHP2) and son of sevenless homolog 1 (SOS1), and shed light on current challenges and opportunities for drug discovery in this field.
Background and Aim: Hashimoto's thyroiditis (HT) is the most common autoimmune thyroid disease, characterised by the destruction of the thyroid gland due to the production of autoantibodies against ...thyroid peroxidase and thyroglobulin. Studies have shown the interaction between some genetic changes in the cell and environmental factors as one of the risk factors for the occurrence of HT. The aim of the present study was to investigate the relationship between the rs61764370 polymorphism in the KRAS gene and the risk of development of HT. Materials and Methods: 120 HT patients and 120 healthy controls who had been matched in regard to age and gender participated in this study. PCR-RFLP method was used to determine the genotypes. Results: The frequency rates of AA, AC and CC genotypes were 87.5%, 8.5% and 6.7% in the control group, and 93.3%, 5.3% and 0.8% in the patient group respectively. Our results showed that the frequency of CC genotype was significantly higher in the control group than that in the patient group (P≤0.05). Conclusion: Our results suggested the protective effect of the CC genotype and C allele of the rs61764370 polymorphism in the KRAS gene on the development of HT.
Therapeutics Targeting Mutant KRAS Thein, Kyaw Z; Biter, Amadeo B; Hong, David S
Annual review of medicine,
01/2021, Letnik:
72, Številka:
1
Journal Article
Recenzirano
Odprti dostop
Aberrations in rat sarcoma (RAS) viral oncogene are the most prevalent and best-known genetic alterations identified in human cancers. Indeed, RAS drives tumorigenesis as one of the downstream ...effectors of EGFR activation, regulating cellular switches and functions and triggering intracellular signaling cascades such as the MAPK and PI3K pathways. Of the three RAS isoforms expressed in human cells, all of which were linked to tumorigenesis more than three decades ago, KRAS is the most frequently mutated. In particular, point mutations in KRAS codon 12 are present in up to 80% of KRAS-mutant malignancies. Unfortunately, there are no approved KRAS-targeted agents, despite decades of research and development. Recently, a revolutionary strategy to use covalent allosteric inhibitors that target a shallow pocket on the KRAS surface has provided new impetus for renewed drug development efforts, specifically against KRAS
G12C
. These inhibitors, such as AMG 510 and MRTX849, show promise in early-phase studies. Nevertheless, combination strategies that target resistance mechanisms have become vital in the war against KRAS-mutant tumors.
G12D mutation is the most common KRAS mutation detected in carcinomas.G12D mutation confers a unique structural conformation that influences downstream signaling and may lead to its potent oncogenic ...activity.Invasive mucinous adenocarcinoma of the lung displays histological features of gastrointestinal cancers and a predominance of KRAS-G12D mutations.Adenocarcinomas of the lung, pancreas and colon driven by KRAS-G12D mutation display an immunosuppressive tumor microenvironment.Mutations in tumor suppressor genes found to co-occur with KRAS-G12D influence tumor biology and response to therapy.KRAS-G12D inhibitors may need to be tailored according to tissue of origin and considered in the context of the co-mutational genomic landscape.
KRAS is the most frequently mutated oncogene in cancer. Activating mutations in codon 12, especially G12D, have the highest prevalence across a range of carcinomas and adenocarcinomas. With inhibitors to KRAS-G12D now entering clinical trials, understanding the biology of KRAS-G12D cancers, and identifying biomarkers that predict therapeutic response is crucial. In this Review, we discuss the genomics and biology of KRAS-G12D adenocarcinomas, including histological features, transcriptional landscape, the immune microenvironment, and how these factors influence response to therapy. Moreover, we explore potential therapeutic strategies using novel G12D inhibitors, leveraging knowledge gained from clinical trials using G12C inhibitors.
KRAS is the most frequently mutated oncogene in cancer. Activating mutations in codon 12, especially G12D, have the highest prevalence across a range of carcinomas and adenocarcinomas. With inhibitors to KRAS-G12D now entering clinical trials, understanding the biology of KRAS-G12D cancers, and identifying biomarkers that predict therapeutic response is crucial. In this Review, we discuss the genomics and biology of KRAS-G12D adenocarcinomas, including histological features, transcriptional landscape, the immune microenvironment, and how these factors influence response to therapy. Moreover, we explore potential therapeutic strategies using novel G12D inhibitors, leveraging knowledge gained from clinical trials using G12C inhibitors.
Although KRAS has long been considered undruggable, direct KRASG12C inhibitors have shown promising initial clinical efficacy. However, the majority of patients still fail to respond. Adaptive ...feedback reactivation of RAS-mitogen-activated protein kinase (MAPK) signaling has been proposed by our group and others as a key mediator of resistance, but the exact mechanism driving reactivation and the therapeutic implications are unclear. We find that upstream feedback activation of wild-type RAS, as opposed to a shift in KRASG12C to its active guanosine triphosphate (GTP)-bound state, is sufficient to drive RAS-MAPK reactivation in a KRASG12C-independent manner. Moreover, multiple receptor tyrosine kinases (RTKs) can drive feedback reactivation, potentially necessitating targeting of convergent signaling nodes for more universal efficacy. Even in colorectal cancer, where feedback is thought to be primarily epidermal growth factor receptor (EGFR)-mediated, alternative RTKs drive pathway reactivation and limit efficacy, but convergent upstream or downstream signal blockade can enhance activity. Overall, these data provide important mechanistic insight to guide therapeutic strategies targeting KRAS.
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•Adaptive RAS-MAPK feedback reactivation occurs following KRASG12C inhibition•RTK-mediated feedback activation of wild-type NRAS and HRAS bypasses KRASG12C•Inhibitor combinations abrogate RAS reactivation, boosting efficacy in KRASG12C CRC•Targeting convergent signaling nodes overcomes adaptive resistance by multiple RTKs
Ryan et al. provide evidence that feedback reactivation of the RAS-MAPK pathway through wild-type NRAS and HRAS, as opposed to a shift in KRASG12C to its active GTP-bound state, can drive adaptive resistance to KRASG12C inhibitors in a KRASG12C-independent manner.
RAS
is one of the most well-known proto-oncogenes. Its gain-of-function mutations occur in approximately 30% of all human cancers. As the most frequently mutated
RAS
isoform, KRAS is intensively ...studied in the past years. Despite its well-recognized importance in cancer malignancy, continuous efforts in the past three decades failed to develop approved therapies for
KRAS
mutant cancer. KRAS has thus long been considered to be undruggable. Encouragingly, recent studies have aroused renewed interest in the development of KRAS inhibitors either directly towards mutant KRAS or against the crucial steps required for KRAS activation. This review summarizes the most recent progress in the exploration of KRAS-targeted anticancer strategies and hopefully provides useful insights for the field.
Continuous efforts in the past three decades failed to develop approved therapies for
KRAS
mutant cancer. Encouragingly, recent progress in the development of KRAS inhibitors either directly towards mutant KRAS or against the crucial steps required for KRAS activation may bring breakthrough for this long-pursued undruggable target.
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