Activating mutations in KRAS are present in 25% of human cancers. When mutated, the KRAS protein becomes constitutively active, stimulating various effector pathways and leading to the deregulation ...of key cellular processes, including the suppression of apoptosis and enhancement of proliferation. Furthermore, mutant KRAS also promotes metabolic deregulation and alterations in the tumor microenvironment. However, some KRAS mutant cancer cells become independent of KRAS for their survival by activating diverse bypass networks that maintain essential survival signaling originally governed by mutant KRAS. The proposed inducers of KRAS independency are the activation of YAP1 and/or RSK-mTOR pathways and co-mutations in SKT11 (LKB1), KEAP1, and NFE2L2 (NRF2) genes. Metabolic reprogramming, such as increased glutaminolysis, is also associated with KRAS autonomy. The presence or absence of KRAS dependency is related to the heterogeneity of KRAS mutant cancers. Epithelial-to-mesenchymal transition (EMT) in tumor cells is also a characteristic phenotype of KRAS independency. Translationally, this loss of dependence is a cause of primary and acquired resistance to mutant KRAS-specific inhibitors. While KRAS-dependent tumors can be treated with mutant KRAS inhibitor monotherapy, for KRAS-independent tumors, we need an improved understanding of activated bypass signaling pathways towards leveraging vulnerabilities, and advancing therapeutic options for this patient subset.
Acute promyelocytic leukemia (APL) is characterized by a series of
retinoic acid receptor (RAR)
fusion genes that lead to the dysregulation of RAR signaling and onset of APL. PML–RARA is the most ...common fusion generated from t(15;17)(q24;q21). In addition, the reciprocal fusion
RARA
–
PML
is present in over 80% of t(15;17) APL cases. The bcr3 types of RARA–PML and RARA–PLZF in particular are reciprocal fusions that contribute to leukemogenesis. Here, we report a variant APL case with t(11;17;15)(q13;q21.2;q24.1). Massive parallel sequencing of patient RNA detected the novel fusion transcripts
RARA
–
SNX15
and
SNX15
–
LINC02255
along with the bcr3 type of
PML
–
RARA
. Genetic analysis revealed that
RARA
–
SNX15L
is an in-frame fusion due to intron retention caused by RNA mis-splicing. RARA–SNX15L consisted mainly of SNX15 domains, including the Phox-homology domain, which has a critical role in protein–protein interactions among sorting nexins and with other partners. Co-immunoprecipitation analysis revealed that RARA–SNX15L is directly associated with SNX15 and with itself. Further studies are needed to evaluate the biological significance of RARA–SNX15L in APL. In conclusion, this is the first report of APL with a complex chromosomal rearrangement involving
SNX15
.
Reoccurring/high-risk neuroblastoma (NB) tumors have the enrichment of non-RAS/RAF mutations along the mitogen-activated protein kinase (MAPK) signaling pathway, suggesting that activation of MEK/ERK ...is critical for their survival. However, based on preclinical data, MEK inhibitors are unlikely to be active in NB and have demonstrated dose-limiting toxicities that limit their use. Here, we explore an alternative way to target the MAPK pathway in high-risk NB. We find that NB models are among the most sensitive among over 900 tumor-derived cell lines to the allosteric SHP2 inhibitor SHP099. Sensitivity to SHP099 in NB is greater in models with loss or low expression of the RAS GTPase activation protein (GAP) neurofibromin 1 (NF1). Furthermore, NF1 is lower in advanced and relapsed NB and NF1 loss is enriched in high-risk NB tumors regardless of MYCN status. SHP2 inhibition consistently blocks tumor growth in high-risk NB mouse models, revealing a new drug target in relapsed NB.
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•We identify neuroblastoma models as sensitive to SHP2 inhibition•SHP099 sensitivity is correlated with low expression of neurofibromin (NF1)•SHP2 inhibitors inhibit pERK in neuroblastoma cells better than in normal cells•NF1 mutation/expression may predict SHP2 inhibitor response in neuroblastoma
In this paper, Cai et al. demonstrate that high-risk neuroblastomas with low NF1 expression are sensitive to SHP2 inhibitors, which may have treatment advantages over MEK inhibitors. Targeting SHP2 blocks neuroblastoma tumor growth. As several SHP2 inhibitors are in clinical trials, SHP2 inhibitors may benefit high-risk NB patients.
Background
Invasive fungal infections (IFIs) represent a potentially fatal complication in patients who undergo allogeneic hematopoietic stem cell transplantation (HSCT) if the initiation of therapy ...is delayed. Some guidelines recommend antifungal prophylaxis or preemptive therapy for these patients depending on the risk of IFIs following allogeneic HSCT. This retrospective study aimed to identify the group of patients who safely undergo allogeneic HSCT with low‐dose fluconazole (FLCZ) prophylaxis (100 mg/day).
Methods
We retrospectively reviewed 107 patients who underwent their first allogeneic HSCT at Nagoya City University Hospital from January 1, 2010, to December 31, 2019. We analyzed the efficacy of low‐dose FLCZ prophylaxis and investigated the relationship between major risk factors and antifungal prophylaxis failure (APF) within 100 days post‐transplant.
Results
Of the 107 patients, 70 received low‐dose FLCZ prophylaxis, showing a cumulative incidence of APF of 37.1% and a proven/probable IFI rate of 4.3%. There were no fungal infection‐related deaths, including Aspergillus infections, in the FLCZ prophylaxis group. In a multivariable analysis, cord blood transplantation (CBT) (subdistribution hazard ratio (SHR), 3.55; 95% confidence interval (CI), 1.44–8.77; p = 0.006) and abnormal findings on lung CT before transplantation (SHR, 2.24; 95% CI, 1.02–4.92; p = 0.044) were independent risk factors for APF in the FLCZ prophylaxis group.
Conclusion
Low‐dose FLCZ prophylaxis is a useful and safe option for patients receiving allogeneic HSCT, except in those undergoing CBT or having any fungal risk features including history of fungal infections, positive fungal markers, and abnormal findings on lung CT before transplantation.
A 15‐year‐old male was diagnosed with acute myeloid leukemia with t(6;9)(p23;q34), a chimeric DEK‐NUP214 fusion gene. He underwent allogeneic bone marrow transplantation (allo‐BMT) from an unrelated ...volunteer donor at first molecular remission. Approximately 5 years after allo‐BMT, multiple bone marrow aspirations showed increased blasts to 63%, which were positive for myeloperoxidase, CD13, CD33, CD56, and CD34. Surprisingly, t(8;21)(q22;q22.1), a chimeric RUNX1‐RUNX1T1 (not DEK‐NUP214) fusion gene, was detected with full donor chimerism. To our best knowledge, this is the first case of a volunteer unrelated donor cell‐derived acute myeloid leukemia harboring a chimeric RUNX1‐RUNX1T1 fusion gene.
Tumor cells evade targeted drugs by rewiring their genetic and epigenetic networks. Here, we identified that inhibition of MAPK signaling rapidly induces an epithelial-to-mesenchymal transition ...program by promoting re-localization of an apical-basal polarity protein, Scribble, in oncogene-addicted lung cancer models. Mis-localization of Scribble suppressed Hippo-YAP signaling, leading to YAP nuclear translocation. Furthermore, we discovered that a RAS superfamily protein MRAS is a direct target of YAP. Treatment with KRAS G12C inhibitors induced MRAS expression, which formed a complex with SHOC2, precipitating feedback activation of MAPK signaling. Abrogation of YAP activation or MRAS induction enhanced the efficacy of KRAS G12C inhibitor treatment in vivo. These results highlight a role for protein localization in the induction of a non-genetic mechanism of resistance to targeted therapies in lung cancer. Furthermore, we demonstrate that induced MRAS expression is a key mechanism of adaptive resistance following KRAS G12C inhibitor treatment.
Metronidazole is an antimicrobial agent used for treating infections caused by anaerobic bacteria and protozoa. Central neurotoxicity is an uncommon and reversible adverse effect of this agent, ...referred to as metronidazole-induced encephalopathy (MIE). Magnetic resonance imaging (MRI) is useful for diagnosing this disorder;T2-weighted and FLAIR images show the selective involvement of bilateral cerebellar dentate nuclei and corpus callosum. It is important that the possibility of MIE be considered when managing patients with ataxia and/or dysarthria undergoing treatment with metronidazole, especially elderly patients or those with chronic illness, who may be more susceptible to toxicity. We present two cases of MIE;one with liver cirrhosis and another aged eighty-eight. Proper diagnosis should be made using brain MRI without delay, because most patients with MIE completely recover after withdrawal of metronidazole. Because some patients have been misdiagnosed with epilepsy because of a lack of abnormalities in MR images at the time of initial diagnosis, it is recommended that brain MRI be repeated in such cases.
Abstract
Background
Various kinds of immune-related adverse events (irAEs) are caused by the usage of immune checkpoint inhibitors (ICI), which occasionally develop to severe conditions such as ...colitis and adrenal gland insufficiency. Since we are unable to anticipate when irAEs may occur, it is crucial to be informed of administration history of ICI on urgent visit.
Methods
We have utilized PDCA cycle Method to improve the quality of countermeasures for irAEs at the emergency room (ER). First, we invented an icon showing the patients treated with ICI on electronic medical records. Second, ICI-specified urgent sets of clinical examination were made to cover the spectrum of irAEs. Third, direct call system to either attending physician or chemotherapy team was established. And then a flow chart to manage irAEs has been prepared since September 2018. Retrospective examination was conducted to check whether the invented system work properly.Results Among 19 patients on ICI, four visited ER during these 4 months.Three cases were seen according to the flow chart, while one with grade 2 diarrhea was found not to undertake any examinations at ER, due to the complete lack of knowledge concerning ICI and irAEs.We informed all of the doctors of this flow chart at doctors’ office committee and gave a lecture for the residents about the significance of irAEs and how to manage these patients at ER.
Conclusions
We are monitoring patients on ICI to check whether their management be performed in safety on urgent visit.
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