Lung Cancer Research Round Up: November 2019
We are in a golden age of lung cancer research, but it can be hard to keep up with all the findings. Our ALK Positive newsletter volunteers have put together this list of some of the recent research being done on lung cancer, with a focus on ALK-positive lung cancer.
TOPIC: Higher BACH1 facilitates metastasis in lung cancer. Ho1 inhibitors as a potential new treatment option.
https://www.cell.com/cell/pdf/S0092-8674(19)30633-6.pdf#secsectitle0020
https://www.cell.com/cell/fulltext/S0092-8674(19)30631-2
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3249911/ (reference for oxidative stress)
https://www.cell.com/cell/pdf/S0092-8674(16)30259-8.pdf (reference for ubiquitin ligase)
Summary: Two articles from the US and Sweden both point to a protein called BACH1, a transcription factor, to be implicated in lung cancer metastasis.
For tumors to grow effectively, cancer cells must overcome barriers of oxidative stress. One of these methods is by lowering stress through reducing a protein called NRF2. Using the antioxidants N-acetylcysteine and vitamin E, the authors showed that metastasis of KRAS-driven lung cancer was actually facilitated. The way metastasis was promoted was by reducing free heme (iron- containing compound important in hemoglobin for iron transport in the blood) and stabilizing the transcription factor BACH1. This transcription factor activates Hexokinase 2 and Gapdh, increases glucose uptake, glycolysis rate, and lactate secretion. Hexokinase 2 is a kinase that works in glucose metabolism in the body. Gadph is an enzyme that works in normal glycolysis (breakdown of sugar into energy used by the cells). In general, BACH1 works in sugar metabolism-related areas in the body. By targeting BACH1, the authors were able to prevent antioxidant-induced metastasis. Conversely, if they increased BACH1, they promoted glycolysis and metastasis even without antioxidants.
Approximately 30% of human lung cancer will acquire mutations in either Keap1 or Nfe2/2, resulting in stabilization of Nrf2, which controls oxidative homeostasis. Oxidative homeostasis is a big topic. Reactive oxygen species such as O2- or OH. or H2O2 have been discussed extensively as free radicals in common literature. Many assume that these radicals may overwhelm the body and affect its ability to regulate itself properly, leading to oxidative stress. Heme triggers the degradation of BACH1 by interacting with ubiquitin ligase Fbxo22. A ubiquitin ligase is a protein that is highly used in cellular processes such as cell cycle progression, transcriptional regulation, DNA repair or signal transduction. When the researchers reduced Keap1 or Fbxo22, metastasis occurred in a BACH1-dependent manner. Metastatic lung cancer patients often have higher levels of Ho1 and BACH1. Ho1 (heme oxygenase-1) is a key protein in maintaining homeostasis. Nrf2 can perhaps activate metastasis via this pathway and Ho1 inhibitors can be used as a new treatment option.
TOPIC: ASCO 2019 presentation on TKI-induced changes in cancer cells
https://meetinglibrary.asco.org/record/163764/abstract
Summary: This is a poster presentation from the 2019 ASCO (American Society of Clinical Oncology) meeting.
A collaborative team from the US, Japan, and China sought to investigate how cancer cells escape TKIs and by what resistance mechanisms. They used a cell line where the originating sample had been obtained from an ALK patient.
When cancer cells are treated with a TKI, many transcription factors are rapidly upregulated within the first 14 days. One of interest is called HOXB3, which is a homebox gene. A homeobox is a transcription factor (a protein that helps in transcribing DNA in the nucleus, so cells can make the protein) that is highly regulated to maintain cell identity and fate. Another protein called TGFb2 level was found to be elevated. This protein can regulate HOXB3 and can change the cell survival signaling through a pathway called BCL-2/BCL-xl. BCL-2/BCL-xl is a well-known cell suicide (apoptosis) pathway. Improper regulation of this pathway can limit the ability of cells to die properly. TGFb2 is also implicated with how a cell can switch its EMT (epithelial-to-mesenchymal transition) identity. Just imagine a donut: epithelial cells are the yummy sugar coating and mesenchymal cells are more toward the middle, dough part of the donut. They perform different things and each has different characteristics. In this transition (EMT), cells change their characteristics inappropriately, and may often be incomplete and potentially become uncontrollable. When the cell line was treated with a TKI, the regulation of HOXB3 was altered, specifically by different methylation (H3K4me3/H3K27me3). A protein called PRC2 is important in this mechanism through its own regulation by EZH2/UTX. EZH2/UTX are master regulatory histone methylation proteins that can change chromatin structures (complex DNA structure inside the cell nucleus). If the EZH2 control is deleted, the cells become ALK TKI-resistant. In addition, when the researchers inhibited UTX control, the cells became more TKI-sensitive.
To summarize:
When treated with a TKI, cancer cells will increase production of TGFb2 which regulates EZH2/UTX. This changes the expression of HOXB3 transcription factors that stop BCL-2/BCL-xl from working properly. As a result, cells are not allowed to die properly.
*Authors note: I only have access to article abstracts.