MDM2 mutation

Notably, the PNC phenotype relies on the expression of EBF3, an early neurogenic transcription factor, which is directly controlled by MYC transcription factors in accessible chromatin sites. Overall our findings indicate that the concomitant presence of genetic alterations, impinging on both cell cycle and p53 pathway control, strongly predisposes GBM to develop a concomitant poorly differentiated primitive phenotype depending on MYC-driven EBF3 transcription in a subset of glioma stem-like progenitor cells.

We also highlight the potential of small molecules e.g. p53 activators like XI-011, Tenovin-1, and Nutlin-3a for the treatment of breast and ovarian cancers. The therapeutic efficacy of natural compounds in amelioration of these two types of cancers is also discussed.

In summary, ENTs arising from GCTs are molecularly heterogeneous; however, a large fraction of testicular ENTs could be stratified by two distinct sets of genetic alterations, including MYCN/MYC amplification with concurrent suppression of the p53 pathway, and activation of the PI3K pathway with co-occurring CDK4 amplification. Moreover, the novel gene fusions identified in a subset of testicular GCT-derived ENTs overlap with molecularly defined tumors of embryonic-type neuroectodermal features in the central nervous system, indicating the potential common driving events for tumorigenesis from different anatomic sites.

Overexpression of MDM2 is a novel resistant mechanism to Osimertinib in EGFR mutant NSCLC. MDM2 utilizes its E3 ligase activity to provoke FBW7 destruction and sequentially leads to MCL-1 stabilization. Cancer cells with aberrant MDM2 state are refractory to apoptosis induction and elicit a resistant phenotype to Osimertinib. Therefore, targeting MDM2 would be a feasible approach to overcome resistance to Osimertinib in EGFR mutant NSCLC.

We sought to evaluate the genomic and transcriptomic landscapes in primary and metastatic germ cell tumors (GCTs; N = 138) to uncover factors that drive cisplatin resistance...PRA-positive PreC GCTs had significantly lower average PSS scores compared to PRA-negative tumors. Lower PSS scores in chemo-naïve tumors were associated with PRAs, suggesting a potential mechanism for platinum resistance.

Whole exome sequencing revealed loss of function mutations in TP53, STK11, PBRM1, SMAD3, FN1, NTRK1, and FANCD2, as well as gain of function mutations in MTOR, BCL11A and COL1A1, along with amplification of CCND3 and MDM2. This mutational landscape halfway between thymic carcinoma (TP53, PBRM1) and hepatoid variant carcinoma of other sites (STK11) suggests that, at some point during carcinogenesis, a switch occurred from an epithelial thymic phenotype to a hepatoid-like one.

In this context, age-related changes in hematopoietic stem cells (HSCs) collaborate with mutant p53 to predispose toward myeloid transformation rather than lymphoma development. Our study unveils new insights into the cooperative impact of HSC age, Trp53 mutations, and Mdm2 haploinsufficiency on clonal hematopoiesis and the development of myeloid malignancies.

P1, N=35, Active, not recruiting, M.D. Anderson Cancer Center | Phase classification: P1b --> P1

The GCTs are remarkably sensitive to cisplatin-based combination chemotherapy; however, resistance to cisplatin develops in up to 8% of tumors and appears to be driven by TP53/MDM2 gene mutations...The mechanisms underlying the development of most tumors have been elucidated; however, additional studies are required to pinpoint the events directing specific characteristics. Advances in identifying specific molecular markers have been seen recently and may be adopted as gold standards in the future.

Other approaches are taking advantage of the progress made in immune-based therapies for cancer. In this Review, we present these ongoing clinical trials and emerging approaches to re-evaluate the current state of knowledge of p53-based therapies for cancer.

Our targeted analysis of MDM2 in a well-characterized cohort of GC patients showed that MDM2 amplification is rare, of no specific histological phenotype, and may not be always mutually exclusive with TP53 mutations. Given the low number of cases, currently, no diagnostic or therapeutic recommendation related to MDM2 amplification can be given for GC of Western origin.

Additionally, NTX-301 treatment increased caspase-8 and cleaved-caspase-8 in AML cells independent of TP53 mutation status, consistence with reports showing caspase-8 hypermethylation in AML and supporting that activation of caspase-8-mediated extrinsic apoptosis as a mechanism of NTX-301 action. In conclusion, our data suggest that NTX-301 has more potent anti-leukemia activities compared to current HMA in clinic and synergizes with venetoclax in venetoclax-resistance and TP53-mutant AML and AML stem/progenitor cells, and warrants clinical evaluation