Related Experiment Video

Updated: Aug 31, 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

8.0K

Loss of VOPP1 Contributes to BET Inhibitor Acquired Resistance in Non-Small Cell Lung Cancer Cells

Lin Sun1,2, Qian Wu1,2, Xia-Juan Huan1,2

  • 1State Key Laboratory of Drug Research, Cancer Research Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.

Molecular Cancer Research : MCR
|August 24, 2022
PubMed

Insights

Drug resistance to bromodomain and extraterminal (BET) inhibitors in non-small cell lung cancer is linked to loss of VOPP1 and increased BCL-2. Combining BET inhibitors with BCL-2 inhibitors overcomes this resistance.

Area of Science:

  • Oncology
  • Molecular Biology
  • Drug Discovery

Background:

  • Bromodomain and extraterminal (BET) protein inhibitors are promising anticancer agents.
  • Acquired drug resistance limits the therapeutic efficacy of BET inhibitors (BETi).
  • Understanding resistance mechanisms is crucial for improving cancer treatment strategies.

Purpose of the Study:

  • To investigate the mechanisms of acquired resistance to BET inhibitors in non-small cell lung cancer (NSCLC).
  • To identify molecular players involved in the development of BETi resistance.
  • To explore therapeutic strategies to overcome BETi resistance.

Main Methods:

  • Generation of drug-resistant NSCLC cell lines (NCI-H1975) through exposure to the BET inhibitor ABBV-075.
  • Analysis of phenotypic changes, RNA expression, and gene mutations in resistant sublines.
  • Functional studies involving VOPP1 manipulation (knockdown, knockout, reconstitution) and BCL-2 inhibition.

Main Results:

  • Resistant cells exhibited cross-resistance to BETis, increased migration, reduced growth, and decreased apoptosis.
  • Loss of vesicular overexpressed in cancer prosurvival protein 1 (VOPP1) and increased BCL-2 were observed in resistant variants.
  • Loss of VOPP1 causally contributed to BETi resistance by upregulating BCL-2, which mediated resistance.
  • Combined treatment with BET inhibitors and BCL-2 inhibitors synergistically sensitized resistant cells.

Conclusions:

  • Established a causal link between VOPP1 loss, BCL-2 upregulation, and BET inhibitor resistance in NSCLC.
  • Identified VOPP1 and BCL-2 as key players in BETi resistance mechanisms.
  • Demonstrated the potential of combining BET inhibitors with BCL-2 inhibitors to overcome drug resistance.

More Related Videos

Implementation of In Vitro Drug Resistance Assays: Maximizing the Potential for Uncovering Clinically Relevant Resistance Mechanisms08:46

Implementation of In Vitro Drug Resistance Assays: Maximizing the Potential for Uncovering Clinically Relevant Resistance Mechanisms

Published on: December 9, 2015

10.7K
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

4.1K

Related Concept Videos

The Retinoblastoma Gene01:20

The Retinoblastoma Gene

Tumor suppressor genes are normal genes that can slow down cell division, repair DNA mistakes, or program the cells for apoptosis in case of irreparable damage. Hence, they play an essential role in preventing the proliferation of damaged cells.
The first-ever tumor suppressor gene called Rb was identified in retinoblastoma - a rare eye tumor in children. In inherited forms of the disease, a child inherits one defective copy of the Rb gene, which predisposes them to retinoblastoma. However,...
4.2K
Loss of Tumor Suppressor Gene Functions01:12

Loss of Tumor Suppressor Gene Functions

Tumor suppressor genes are normal genes that can slow down cell division, repair DNA mistakes, or program the cells for apoptosis in case of irreparable damage. Hence, they play an essential role in preventing the proliferation of damaged cells.
When the tumor suppressor genes develop mutations or are lost, cells start growing out of control, leading to cancer. However, a single functional copy of the tumor suppressor gene is enough for the cells to maintain their normal functions and cell...
5.1K
Adaptive Mechanisms in Cancer Cells02:53

Adaptive Mechanisms in Cancer Cells

Cancer cells accumulate genetic changes at an abnormally rapid rate due to the defects in the DNA repair mechanisms. From an evolutionary perspective, such genetic instability is advantageous for cancer development. Mutant cell lines accumulate a series of beneficial mutations that contribute to their progression into cancer.
Some of the advantages that cancer cells have on normal cells include - enhanced ability to divide without terminally differentiating, induce new blood vessel formation,...
5.9K
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...
3.9K
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
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...
3.9K