Related Experiment Video

Updated: Jun 21, 2025

Establishment and Characterization of Three Afatinib-resistant Lung Adenocarcinoma PC-9 Cell Lines Developed with Increasing Doses of Afatinib
09:38

Establishment and Characterization of Three Afatinib-resistant Lung Adenocarcinoma PC-9 Cell Lines Developed with Increasing Doses of Afatinib

Published on: June 26, 2019

7.9K

A first-in-class selective inhibitor of EGFR and PI3K offers a single-molecule approach to targeting adaptive

Christopher E Whitehead1,2, Elizabeth K Ziemke1, Christy L Frankowski-McGregor1

  • 1Department of Radiology, University of Michigan, Ann Arbor, MI, USA.

Nature Cancer
|July 11, 2024
PubMed

Insights

A novel drug, MTX-531, effectively targets cancer resistance mechanisms by inhibiting epidermal growth factor receptor and PI3K. This drug shows promise for durable tumor regressions and improved survival in preclinical models.

Area of Science:

  • Oncology
  • Pharmacology
  • Molecular Biology

Background:

  • Adaptive resistance mechanisms limit targeted cancer therapies.
  • Epidermal growth factor receptor (EGFR) and phosphatidylinositol 3-OH kinase (PI3K) are key drivers of resistance.

Purpose of the Study:

  • To evaluate the pharmacological profile of MTX-531, a novel dual inhibitor of EGFR and PI3K.
  • To assess the efficacy and tolerability of MTX-531 in preclinical cancer models.

Main Methods:

  • Computational drug design and cocrystal structural analyses to assess specificity.
  • In vivo studies using patient-derived xenograft (PDX) models of head and neck and colorectal cancers.
  • Combination therapy with MEK or KRAS inhibitors.

Main Results:

  • MTX-531 demonstrated low-nanomolar potency and high specificity for EGFR and PI3K.
  • Monotherapy with MTX-531 induced tumor regressions in head and neck cancer PDX models.
  • Combination therapy led to durable regressions and increased survival in colorectal cancer PDX models.
  • MTX-531 was well-tolerated and did not cause hyperglycemia, unlike other PI3K inhibitors, due to weak agonism of PPAR-γ.

Conclusions:

  • MTX-531 is a potent and specific dual inhibitor of EGFR and PI3K with promising preclinical efficacy.
  • Its unique mechanism, mitigating hyperglycemia, suggests a favorable therapeutic index for cancer treatment.

More Related Videos

Establishing Dual Resistance to EGFR-TKI and MET-TKI in Lung Adenocarcinoma Cells In Vitro with a 2-step Dose-escalation Procedure09:38

Establishing Dual Resistance to EGFR-TKI and MET-TKI in Lung Adenocarcinoma Cells In Vitro with a 2-step Dose-escalation Procedure

Published on: August 11, 2017

8.8K
A Rapid Screening Workflow to Identify Potential Combination Therapy for GBM using Patient-Derived Glioma Stem Cells05:29

A Rapid Screening Workflow to Identify Potential Combination Therapy for GBM using Patient-Derived Glioma Stem Cells

Published on: March 28, 2021

2.8K

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...
7.5K
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...
3.5K
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...
6.4K
Treatment for Pulmonary Arterial Hypertension: Receptor Tyrosine Kinase Inhibitors and Calcium Channel Blockers01:26

Treatment for Pulmonary Arterial Hypertension: Receptor Tyrosine Kinase Inhibitors and Calcium Channel Blockers

Receptor tyrosine kinase inhibitors (TKIs) and calcium channel blockers (CCBs) are two critical categories of drugs employed in the treatment of pulmonary artery hypertension (PAH). PAH is a disease that causes high blood pressure in the pulmonary arteries, resulting in chest pain, fatigue, and shortness of breath.
TKIs, such as imatinib (Gleevec), are particularly effective in tackling the growth and mitogenic factors that become upregulated in PAH patients. These factors contribute to the...
156
Inhibition of Cdk Activity02:34

Inhibition of Cdk Activity

The orderly progression of the cell cycle depends on the activation of Cdk protein by binding to its cyclin partner. However, the cell cycle must be restricted when undergoing abnormal changes. Most cancers correlate to the deregulated cell cycle, and since Cdks are a central component of the cell cycle, Cdk inhibitors are extensively studied to develop anticancer agents. For instance, cyclin D associates with several Cdks, such as Cdk 4/6, to form an active complex. The cyclin D-Cdk4/6 complex...
4.7K
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...
4.9K