TP53 R175H

Mutational hotspots are a recurrent feature in both genes which, due to positive selection during tumorigenesis, can be potentially exploited by targeted treatments, as has been demonstrated by the US Food and Drug Administration (FDA)-approved PI3K inhibitor alpelisib in advanced hormone-receptor positive (HR+) breast cancer... The AGENA ClearSEEK PIK3CA and TP53 Panels combine low hands-on time requirements with accurate data assessment, and provide a reliable tool for clinical trial evaluation of known actionable PIK3CA mutations and response to PI3K inhibitors in breast cancer, as well as for investigating the oncogenic activities of TP53 hotspot mutations and patient selection e.g., for cell cycle targeting therapies.

This result revealed the strong influence the cell-of-origin plays in glioma heterogeneity. Our platform is highly adaptable and allows for modular and systematic interrogation of how cell-of-origin shape the tumor landscape.

Our findings indicate a high frequency of TP53 variants in CRC patients from Rwanda. Importantly, these variants are enriched in the CMS2 subtype. This study, representing the second investigation into molecular alterations in patients with CRC from Rwanda and the first to explore TP53 mutations and CMS classification, provides valuable insights into the molecular landscape of CRC in this understudied population.

This combination induced replicative stress and caspase-mediated cell death and was highly effective in resistant/refractory patient samples with TP53 deletion and/or mutation and in TP53 -/- NCI-H929 xenografted NOD-scid IL2Rgamma mice. Our in vitro, ex vivo, and in vivo data provide the rationale for combined CTPS1 and ATR inhibition for the treatment of p53-deficient patients.

These alterations in cell motility were closely associated with actin cytoskeleton restructuring, favoring γ-actin, and coincided with ERK1/2-mediated signaling activation, unveiling an innovative regulatory mechanism in malignancy progression. Cancer cell aggressiveness, driven by actin cytoskeleton reorganization and a shift towards γ-actin predominance, may be regulated by p53 dysfunction, thereby providing novel insight into tumor progression mechanisms.

These data indicate that epigenetic silencing suppresses MLH1 transcription, induces the loss of MLH1 protein, abrogates mismatch repair, and drives genomic instability in naturally occurring CRC in rhesus macaques. We consider this spontaneous, uninduced CRC in immunocompetent, treatment-naïve rhesus macaques to be a uniquely informative model for human CRC.

Moreover, CORO1A overexpression resulted in the downregulation of p-p38 levels. Molecular docking studies further revealed that tea polyphenols can inhibit breast cancer proliferation by binding to p53.

Low intensity induction (Lo) included hypomethylating agent with/without venetoclax... The clinical outcomes of TP53 mutated MDS/AML remains discouraging. Select patients may benefit from HSCT but a large proportion of patients still experience post-transplant relapse. Better treatment strategy is direly needed for this distinct patient population.

Hazard ratios and p-values were computed via Cox regression when comparing OS relative to date of advanced diagnosis and PFS on subsets who received 1st line FOLFIRINOX (FFX) or 1st line gemcitabine/nab-paclitaxel (GA)... TP53 mutations correlated with worse prognosis in advanced PDAC. Potential predictive associations favoring FFX over GA in the TP53 LOF subgroup (but not in GOF or WT subgroups) warrant further exploration. >

DN TP53 mutations correlated with worse prognosis in prostate cancer patients and higher metastatic potential, which could be counteracted by APR-246 treatment suggesting a potential future therapeutic avenue.

Mechanism-based combinations with XPO-1, MDM2, and Bcl-2 inhibitors induce massive apoptosis. PC14586 is presently in early clinical trials.

When used sequentially with LBS-007, hydroxyurea provided a robust response yielding GI50's between 1 and 3 nM for LBS-007, effectively blocking DNA replication origins (LBS-007) and inducing fork stalls (HU)...Most impressively, the combination of LBS-007 and venetoclax was exponentially enhanced when used in conjunction with ceralasertib (4.8 pM)...Our results identify a unique and potentially efficacious strategy to treat one of the most difficult to treat subtypes of AML. These findings will provide the rationale for potential clinical trials using CDC7 inhibition in p53 mutated or R/R AML.