Related Experiment Video

Updated: Apr 6, 2026

A Combined 3D Tissue Engineered In Vitro/In Silico Lung Tumor Model for Predicting Drug Effectiveness in Specific Mutational Backgrounds
13:34

A Combined 3D Tissue Engineered In Vitro/In Silico Lung Tumor Model for Predicting Drug Effectiveness in Specific Mutational Backgrounds

Published on: April 6, 2016

10.8K

Synergistic effects through targeting the PI3K and IGFR pathways in treating lung cancer carrying activation

Mohamed Abd El-Salam1, Wu Chen2, Yan Tang3

  • 1Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA; VA Boston Healthcare System, Boston, MA, USA; Institute for Research in Biomedicine (IRB) Barcelona, The Barcelona Institute of Science and Technology, Barcelona, Spain; Department of Pharmacognosy, Faculty of Pharmacy, Delta University for Science and Technology, Gamasa, Egypt; GIHDiNuC Research Group, Department of Health, School of Health Sciences of TecnoCampus, Pompeu Fabra University, Barcelona, Spain.

Translational Oncology
|April 4, 2026
PubMed
Abstract

Insights

Dual blockade of PI3K and IR/IGF-1R signaling shows promise for overcoming resistance in PIK3CA-mutant non-small cell lung cancer (NSCLC). This combination therapy demonstrated significant anti-tumor effects and prolonged survival in preclinical models.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • PI3K/AKT pathway alterations are common in lung cancer, driving tumor progression and resistance to targeted therapies.
  • Compensatory activation of insulin receptor (IR) and insulin-like growth factor-1 receptor (IGF-1R) signaling limits the efficacy of PI3K inhibitors in PIK3CA-mutant non-small cell lung cancer (NSCLC).

Purpose of the Study:

  • To investigate whether dual blockade of PI3K and IR/IGF-1R signaling can overcome adaptive resistance in PIK3CA-mutant NSCLC.
  • To evaluate the synergistic effects of combining PI3K and IR/IGF-1R inhibitors on cancer cell proliferation, migration, and invasion.
  • To assess the therapeutic efficacy and toxicity of this combination strategy in a patient-derived xenograft (PDX) model.

Main Methods:

  • Utilized PIK3CA E545K-mutant H460 NSCLC cells and a PIK3CA E545K-mutant lung squamous cell carcinoma PDX model.
  • Assessed effects of combining a PI3K/AKT inhibitor with ceritinib (an ALK, IR/IGF-1R inhibitor).
  • Performed functional assays (colony formation, wound healing, Matrigel invasion), Western blot, RNA-seq, and qRT-PCR.

Main Results:

  • Dual PI3K and IR/IGF-1R inhibition exhibited synergistic anti-proliferative, anti-migratory, and anti-invasive effects in vitro.
  • Combination therapy in the PDX model significantly prolonged overall survival with no added systemic toxicity.
  • Transcriptomic analysis identified the TNF-α/NF-κB axis as a potential mechanism of acquired resistance.

Conclusions:

  • Concurrent targeting of PI3K and IR/IGF-1R signaling effectively overcomes adaptive resistance in PIK3CA-mutant NSCLC.
  • This dual-targeting strategy warrants further clinical investigation for NSCLC treatment.
Keywords:
CeritinibDrug resistanceIR/IGF-1R signalingKetogenic dietLung cancerPI3K/AKT pathwayPIK3CA mutation

More Related Videos

Utilizing 18F-FDG PET/CT Imaging and Quantitative Histology to Measure Dynamic Changes in the Glucose Metabolism in Mouse Models of Lung Cancer06:51

Utilizing 18F-FDG PET/CT Imaging and Quantitative Histology to Measure Dynamic Changes in the Glucose Metabolism in Mouse Models of Lung Cancer

Published on: July 21, 2018

18.9K
Network Pharmacology Prediction and Experimental Validation of Trichosanthes-Fritillaria thunbergii Action Mechanism Against Lung Adenocarcinoma13:18

Network Pharmacology Prediction and Experimental Validation of Trichosanthes-Fritillaria thunbergii Action Mechanism Against Lung Adenocarcinoma

Published on: March 3, 2023

1.9K

Related Concept Videos

Targeted Cancer Therapies02:57

Targeted Cancer Therapies

The targeted cancer therapies, also known as “molecular targeted therapies,” take advantage of the molecular and genetic differences between the cancer cells and the normal cells. It needs a thorough understanding of the cancer cells to develop drugs that can target specific molecular aspects that drive the growth, progression, and spread of cancer cells without affecting the growth and survival of other normal cells in the body.
There are several types of targeted therapies against...
9.1K
PI3K/mTOR/AKT Signaling Pathway01:22

PI3K/mTOR/AKT Signaling Pathway

The mammalian target of rapamycin  (mTOR) is a serine/threonine kinase that regulates growth, proliferation, and cell survival in response to hormones, growth factors, or nutrient availability. This kinase exists in two structurally and functionally distinct forms: mTOR complex 1  (mTORC1) and mTOR complex 2  (mTORC2). The first form (mTORC1) is composed of a rapamycin-sensitive Raptor and proline-rich Akt substrate, PRAS40. In contrast,  mTORC2 consists of a...
6.4K
Combination Therapies and Personalized Medicine02:50

Combination Therapies and Personalized Medicine

Combining two or more treatment methods increases the life span of cancer patients while reducing damage to vital organs or tissue from the overuse of a single treatment. Combination therapy also targets different cancer-inducing pathways, thus reducing the chances of developing resistance to treatment.
The combination of the drug acetazolamide and sulforaphane is a good example of combination therapy to treat cancer. The cells in the interior of a large tumor often die due to the hypoxic and...
6.3K
Interactions Between Signaling Pathways01:19

Interactions Between Signaling Pathways

Signaling cascades usually lack linearity. Multiple pathways interact and regulate one another, allowing cells to integrate and respond to diverse environmental stimuli.
Convergence and divergence, and cross-talk between signaling pathways
Two distinct signaling pathways can converge on a single functional unit, which may either be a single protein or a complex of proteins. The response is either functionally distinct or synergistic between the two pathways but different from the response...
7.9K
Mitogens and the Cell Cycle02:38

Mitogens and the Cell Cycle

Mitogens and their receptors play a crucial role in controlling the progression of the cell cycle. However, the loss of mitogenic control over cell division leads to tumor formation. Therefore, mitogens and mitogen receptors play an important role in cancer research. For instance, the epidermal growth factor (EGF) - a type of mitogen and its transmembrane receptor (EGFR), decides the fate of the cell's proliferation. When EGF binds to EGFR, a member of the ErbB family of tyrosine kinase...
8.4K
mTOR Signaling and Cancer Progression03:03

mTOR Signaling and Cancer Progression

The mammalian target of rapamycin or mTOR protein was discovered in 1994 due to its direct interaction with rapamycin. The protein gets its name from a yeast homolog called TOR. The mTOR protein complex in mammalian cells plays a major role in balancing anabolic processes such as the synthesis of proteins, lipids, and nucleotides and catabolic processes, such as autophagy in response to environmental cues, such as availability of nutrients and growth factors.
The mTOR pathway or the...
5.1K