Evidence map›Paper›PMID 41456631›Full record

ArticleActa biomaterialia2026

Dual Inhibition of KRAS G12D and PI3K/BRD4 signaling overcomes therapeutic resistance in pancreatic cancer.

Yashwardhan Ghanwatkar, Sohan Mahto, Ajaykumar Chittipolu, Raghu Ramanathan, Prakash Shrestha, Ram I Mahato

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Acta biomaterialia, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 4 papers.

0numbers the graph read from it
0cells of the map it votes in
4citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

4 citing papers in PubMed.

  1. Review
  2. Targeted therapeutic strategies forTranslational lung cancer research · 2026
    Review
  3. Review
  4. Review
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

6 authors.

Yashwardhan GhanwatkarDepartment of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, NE 68198, USA.
Sohan MahtoDepartment of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, NE 68198, USA.
Ajaykumar ChittipoluDepartment of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, NE 68198, USA.
Raghu RamanathanDepartment of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, NE 68198, USA.
Prakash ShresthaDepartment of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, NE 68198, USA.
Ram I MahatoDepartment of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, NE 68198, USA. Electronic address: ram.mahato@unmc.edu.

Funding

Nanomedicine of Hedgehog and AKT/ERK Dual Inhibitors for Pancreatic CancerR01CA266759 · NCI · UNIVERSITY OF NEBRASKA MEDICAL CENTER · PI Ram I. Mahato · 2022 to 2026
$2.2M
NCI NIH HHS R01 CA266759
6 · The paper itself

Abstract

Oncogenic KRAS G12D mutations drive pancreatic ductal adenocarcinoma (PDAC) but face therapeutic resistance from pathway reactivation. We synthesized MDP5, a dual BRD4/PI3K inhibitor, to address this issue. When combined with the KRAS G12D inhibitor MRTX1133, MDP5 resensitized resistant cancer cells. This combination synergistically enhanced apoptosis and proliferation inhibition, outperforming the standard-of-care, Gemcitabine (GEM). This dual-inhibition strategy effectively counters resistance mechanisms in KRAS-mutant PDAC, offering a promising therapeutic approach. We formulated MUC4-targeted polymeric nanoparticles co-loading MRTX1133 (8.3%) and MDP5 (7.4%) that exhibited pH-responsive release and uniform morphology. This targeted delivery translated to superior anti-tumor efficacy, as the combination of NPs markedly reduced tumor burden more effectively than single-drug treatments or a polymer-Gemcitabine conjugate. Importantly, this potent therapeutic effect was achieved without inducing detectable liver highlighting the potential, safe, and effective cancer therapy. Mechanistically, dual targeting reduced p-AKT and YAP1, depleted CD44

Indexed as

Carcinoma, Pancreatic DuctalCell Cycle ProteinsDrug Resistance, NeoplasmPancreatic NeoplasmsPhosphatidylinositol 3-KinasesProto-Oncogene Proteins p21(ras)Signal TransductionTranscription FactorsAnimalsApoptosisBromodomain Containing ProteinsCell Line, TumorDeoxycytidineGemcitabineHumansMiceBRD4 protein, humanBromodomain Containing ProteinsCell Cycle ProteinsDeoxycytidineGemcitabineKRAS protein, humanPhosphatidylinositol 3-KinasesProto-Oncogene Proteins p21(ras)Transcription FactorsBRD4GemcitabineKRAS G12DMUC4NanoparticlesPancreatic cancerPI3K

Identifiers

PMID41456631
PMCPMC13207627

What OpenQuestion holds

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Registered trials

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.