Biology subjects

Alruwaili, M.

Publications and source records attributed to Alruwaili, M..

4 recordsLinked to original sources

bioRxiv2025

A Sequential Triple-Drug Strategy for Selective Targeting of p53-Mutant Cancers

The tumor suppressor TP53 gene (p53) is mutated in most human malignancies; however, existing treatment options are largely ineffective, lack selectivity, and cause toxic side effects. To address these clinical problems, we developed a sequential triple-drug strategy for p53 mutant cancer cells. Here we show that a combination of a thymidine analogue (TAS102) plus PARP inhibitor (PARPi) promotes formation of DNA double-strand breaks (DSBs) and G2-arrest specifically in p53 mutant cancer cells. Transcriptome analysis revealed that TAS102-PARPi treatment of p53 mutant cells did not repress DNA replication but activated DSB repair and blocked the mitotic program, consistent with G2-arrest. In contrast, TAS102-PARPi treatment of normal p53 wild-type cells resulted in a temporal G1-arrest and rapid recovery of cell cycle capacity after drug withdrawal. In p53 mutant cancer cells, subsequent blocking of a G2-checkpoint kinase, such as WEE1, released these G2-arrested cells into mitosis, leading to massive cell death. Delayed administration of a G2-kinase inhibitor provides time for p53 wild-type cells to repair DNA, thereby minimizing toxicity to normal tissues. This sequential triple-drug strategy exhibited robust efficacy in preclinical models of colorectal and pancreatic cancers and was well tolerated in mice. Together, our findings illustrate a promising triple-drug strategy for targeting p53 mutant malignancies.

cancer biology↗

bioRxiv2025

p38 blockade reverses the immune suppressive tumor microenvironment in metastatic breast cancer

Metastatic breast cancer (MBC) is a life-threatening disease with limited therapeutic options. The immune suppressive tumor microenvironment (TME) limits the potency of the antitumor immune response and facilitates disease progression and metastasis. Our current study demonstrates that p38 is a druggable target in the TME that regulates the outcome of the immune-tumor interaction. The study revealed that systemic blockade of p38 reduces metastasis, and this anti-metastatic response is negated by depletion of CD8+ T cells. Single-cell transcriptomic analysis of the immune-TME showed that pharmacological p38 inhibition (p38i) or tumor-specific inactivation of p38 by CRISPR/Cas9 (p38KO) resulted in a less exhausted and more activated CD8+ T cell phenotype. Immunophenotyping analyses demonstrated that p38 blockade reduced the expression of multiple inhibitory receptors on CD8+ T cells (i.e., PD-1, LAG-3, CTLA-4), indicating a reversal of immune exhaustion and enhanced immune activation systemically and in the TME. In contrast, p38 blockade did not exhibit inhibitory effects on T cells in proliferation assays in vitro and did not affect the proportion of regulatory T cells in vivo. The major negative impact of p38 blockade in vivo was on the myeloid populations, such as myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages (TAMs). Further, tumor p38 activity was required for the expression of cytokines/chemokines and tumor-derived exosomes with high chemotactic capacity for myeloid cells. Altogether, this study highlights a previously unrecognized p38-driven pathway that promotes an immune suppressive TME and metastasis, and that therapeutic blockade of p38 has important implications for improving antitumor immunity and patient outcomes. STATEMENT OF SIGNIFICANCEThis study highlights a previously unrecognized p38-driven tumor pathway that promotes an immune suppressive microenvironment and metastasis, and that therapeutic blockade of p38 has important implications for improving antitumor immunity and patient outcomes.

cancer biology↗

bioRxiv2023

SARS-CoV-2 NSP12 associates with the TRiC complex and the P323L substitution is a host adaption.

SARS-CoV-2 emerged into the human population in late 2019 and human to human transmission has dominated the evolutionary landscape and driven the selection of different lineages. The first major change that resulted in increased transmission was the D614G substitution in the spike protein. This was accompanied by the P323L substitution in the viral RNA dependent RNA polymerase (RdRp) (NSP12). Together, with D614G these changes are the root of the predominant global SARS-CoV-2 landscape. Here, we found that NSP12 formed an interactome with cellular proteins. The functioning of NSP12 was dependent on the T-complex protein Ring Complex, a molecular chaperone. In contrast, there was differential association between NSP12 variants and components of a phosphatase complex (PP2/PP2A and STRN3). Virus expressing NSP12L323 was less sensitive to perturbations in PP2A and supports the paradigm that ongoing genotype to phenotype adaptation of SARS- CoV-2 in humans is not exclusively restricted to the spike protein.

microbiology↗

bioRxiv2020

Amplicon and metagenomic analysis of MERS-CoV and the microbiome in patients with severe Middle East respiratory syndrome (MERS)

Middle East Respiratory Syndrome coronavirus (MERS-CoV) is a zoonotic infection that emerged in the Middle East in 2012. Symptoms range from mild to severe and include both respiratory and gastrointestinal illnesses. The virus is mainly present in camel populations with occasional spill overs into humans. The severity of infection in humans is influenced by numerous factors and similar to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) underlying health complications can play a major role. Currently, MERS-CoV and SARS-CoV-2 are co-incident in the Middle East and a rapid way is required of sequencing MERS-CoV to derive genotype information for molecular epidemiology. Additionally, complicating factors in MERS-CoV infections are co-infections that require clinical management. The ability to rapidly characterise these infections would be advantageous. To rapidly sequence MERS-CoV, we developed an amplicon-based approach coupled to Oxford Nanopore long read length sequencing. The advantage of this approach is that insertions and deletions can be identified - which are the major drivers of genotype change in coronaviruses. This and a metagenomic approach were evaluated on clinical samples from patients with MERS. The data illustrated that whole genome or near whole genome information on MERS-CoV could be rapidly obtained. This approach provided data on both consensus genomes and the presence of minor variants including deletion mutants. Whereas, the metagenomic analysis provided information of the background microbiome.

molecular biology↗