Related Experiment Video

Updated: Jan 13, 2026

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

8.4K

ZDHHC11-mediated AXL palmitoylation promotes osimertinib resistance in non-small-cell lung cancer

He Cui1,2, Xueting Cai3, Qiang Qian1

  • 1Jiangsu Key Laboratory for Pharmacology and Safety Research of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, Jiangsu, China.

Proceedings of the National Academy of Sciences of the United States of America
|October 28, 2025
PubMed

Insights

ZDHHC11 palmitoylation drives resistance to osimertinib in EGFR-mutant non-small-cell lung cancer (NSCLC) by activating AXL. Inhibiting ZDHHC11 may restore sensitivity in resistant NSCLC patients.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • Receptor tyrosine kinase (RTK) pathway rewiring is key to acquired resistance against EGFR tyrosine kinase inhibitors (TKIs) in EGFR-mutant non-small-cell lung cancer (NSCLC).
  • Posttranslational modifications, including palmitoylation, are implicated in activating bypass signaling networks, but their specific role in TKI resistance is unclear.
  • ZDHHC palmitoyl acyltransferases mediate protein palmitoylation, a process influencing protein localization and function.

Purpose of the Study:

  • To investigate the role of ZDHHC11-mediated palmitoylation in osimertinib resistance in EGFR-mutant NSCLC.
  • To identify the substrate(s) of ZDHHC11 involved in promoting resistance.
  • To evaluate ZDHHC11 inhibition as a therapeutic strategy.

Main Methods:

  • Analysis of patient samples and cell lines.
  • In vitro and in vivo functional studies.
  • Western blotting, immunoprecipitation, and AXL knockout experiments.
  • Pharmacological inhibition of ZDHHC11 using 2-bromopalmitate.

Main Results:

  • ZDHHC11 upregulation was found to reduce tumor cell sensitivity to osimertinib, promoting a malignant phenotype.
  • AXL receptor tyrosine kinase was identified as a critical substrate, with ZDHHC11 catalyzing its palmitoylation at Cys869.
  • Palmitoylation induced AXL plasma membrane retention and constitutive activation, triggering downstream PI3K-AKT signaling.
  • AXL knockout abrogated ZDHHC11-driven resistance, and 2-bromopalmitate treatment augmented osimertinib's antitumor effects.

Conclusions:

  • ZDHHC11-mediated palmitoylation is a key mechanism conferring osimertinib resistance in EGFR-mutant NSCLC.
  • The ZDHHC11-AXL signaling axis is crucial for this resistance mechanism.
  • Targeting the ZDHHC11-AXL axis presents a potential therapeutic strategy for osimertinib-resistant NSCLC.
Keywords:
AXLOsimertinibPalmitoylationZDHHC11non-small-cell lung cancer

More Related Videos

Profiling Sensitivity to Targeted Therapies in EGFR-Mutant NSCLC Patient-Derived Organoids08:52

Profiling Sensitivity to Targeted Therapies in EGFR-Mutant NSCLC Patient-Derived Organoids

Published on: November 22, 2021

4.5K
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

9.2K

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...
8.6K
Abnormal Proliferation02:23

Abnormal Proliferation

Under normal conditions, most adult cells remain in a non-proliferative state unless stimulated by internal or external factors to replace lost cells. Abnormal cell proliferation is a condition in which the cell's growth exceeds and is uncoordinated with normal cells. In such situations, cell division persists in the same excessive manner even after cessation of the stimuli, leading to persistent tumors. The tumor arises from the damaged cells that replicate to pass the damage to the...
5.1K
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...
3.7K
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...
4.6K