Related Experiment Video

Updated: Aug 12, 2025

Author Spotlight: Assessing the Potential of Circulating Tumor Cells in Leptomeningeal Disease Research
06:25

Author Spotlight: Assessing the Potential of Circulating Tumor Cells in Leptomeningeal Disease Research

Published on: March 29, 2024

968

MYC-mediated resistance to trametinib and HCQ in PDAC is overcome by CDK4/6 and lysosomal inhibition

Mark R Silvis1, Dilru Silva1,2, Riley Rohweder1

  • 1Huntsman Cancer Institute, University of Utah , Salt Lake City, UT, USA.

The Journal of Experimental Medicine
|January 31, 2023
PubMed

Insights

Pancreatic cancer patients resistant to MEK/autophagy inhibitors show increased c-MYC. Combining palbociclib with hydroxychloroquine overcomes this resistance, suggesting a new treatment strategy for pancreatic ductal adenocarcinoma.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Research

Background:

  • The KRAS>RAF>MEK1/2>ERK1/2 pathway is crucial in pancreatic ductal adenocarcinoma (PDAC).
  • Combined MEK1/2 (trametinib) and autophagy (chloroquine/hydroxychloroquine) inhibition shows anti-tumor effects in PDAC.
  • Resistance to trametinib/hydroxychloroquine (T/HCQ) therapy limits clinical benefit.

Purpose of the Study:

  • Investigate mechanisms of T/HCQ resistance in PDAC.
  • Identify biomarkers associated with T/HCQ resistance.
  • Evaluate novel therapeutic strategies to overcome T/HCQ resistance.

Main Methods:

  • Analysis of DNA copy number gains in resistant PDAC.
  • Ectopic c-MYC expression in PDAC cell lines.
  • Preclinical testing of palbociclib (P) in combination with hydroxychloroquine (HCQ).
  • Treatment of a PDAC patient with P/HCQ.

Main Results:

  • Focal DNA copy number gains of c-MYC correlate with primary and acquired T/HCQ resistance.
  • Elevated c-MYC expression confers T/HCQ resistance in PDAC cell lines.
  • Palbociclib (P) induces autophagy and overcomes c-MYC-mediated T/HCQ resistance.
  • P/HCQ treatment promotes regression of T/HCQ-resistant PDAC tumors and shows a biochemical response in a patient.

Conclusions:

  • Elevated c-MYC is a marker and mediator of T/HCQ resistance in PDAC.
  • Combining palbociclib with hydroxychloroquine is a potential strategy to overcome c-MYC-driven T/HCQ resistance.
  • This combination therapy warrants further investigation for PDAC treatment.

More Related Videos

Pooled shRNA Library Screening to Identify Factors that Modulate a Drug Resistance Phenotype14:51

Pooled shRNA Library Screening to Identify Factors that Modulate a Drug Resistance Phenotype

Published on: June 17, 2022

3.3K
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

8.9K

Related Concept Videos

Treatment Resistant Cancers02:56

Treatment Resistant Cancers

Cancer is the second leading cause of death in the United States. A cancer cell is genetically unstable and hence can mutate faster. They can also modify their microenvironment and escape immune surveillance. The difficulties in treating cancer are further compounded by the emergence of rapid resistance to anticancer drugs. The most common ways to attain resistance in cancer cells include alteration in drug transport and metabolism, modification of drug target, elevated DNA damage response, or...
3.4K
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...
4.9K
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...
5.0K
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...
7.8K
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...
3.8K