This week we profile a recent publication in Cell Reports from first author Fraser Johnson
(pictured, back row, second from right) in the lab of Dr. William Lockwood
(back row, far right) at the BC Cancer Research Institute and UBC.
Can you provide a brief overview of your lab’s current research focus?
Our lab is focused on studying the biological basis of lung cancer initiation, progression and response to therapy. We utilize different approaches to address this, from sequencing patient tumours to performing functional screens in cell lines and genetically engineered mouse model systems. Through integration of these different platforms, we investigate a wide variety of questions including why some patients are more susceptible to lung cancer development, how drug resistance manifests and can be circumvented, and how specific mutations drive lung cancer and immune response, just to name a few. We even have a project investigating whether smoking cannabis is associated with lung carcinogenesis.
What is the significance of the findings in this publication?
This publication comes from a long standing interest our lab has had in using chemical screening to interrogate lung cancer biology. Our close collaborators at Memorial Sloan Kettering performed a high-throughput screen of a panel of ~200,000 small molecules, searching for chemicals that could inhibit the growth of lung cancer, but not normal, cell lines. Through this, they identified a compound called Lung Cancer Screen 3 (LCS3) as a promising candidate in this context. However, the way LCS3 killed lung cancer cells while sparing normal cells remained unknown. Fraser Johnson, a PhD candidate in our lab, was interested in investigating the mechanism of action of LCS3. Co-supervised by Gregg Morin, head of the proteomic core at the Genome Sciences Centre, Fraser decided to optimize and employ a cutting edge approach called Thermal Proteomic Profiling (TPP) to address this. This method takes advantage of shifts in melting temperatures of proteins when bound to a small molecule, allowing the potential identification of drug binders on a global scale. Through this novel approach – and integrating with data on the transcriptional and molecular changes induced by LCS3 treatment in lung cancer cells – he identified two proteins involved in mediating cell redox homeostasis (GSR and TXNRD1) as potential targets of LCS3. Enzymatic assays confirmed that LCS3 inhibited the function of these two proteins, and functional studies demonstrated that their dual inhibition kills lung cancer cells through the induction of reactive oxygen species. Lastly, a genome-wide CRISPR screen confirmed the role of redox machinery in meditating sensitivity to LCS3. This work suggests that small molecules based like LCS3 that target GSR and TXNRD1 may be effective in the treatment of lung cancer. Furthermore, it provides a flexible template for uncovering the molecular targets of novel compounds identified by high-throughput screening, addressing a major bottleneck in chemical biology studies.
What are the next steps for this research?
Although it is effective in vitro, additional work will be required to make derivatives of LCS3 with pharmacological properties suitable for clinical use. We plan to address this in collaboration with medicinal chemists and using the resulting optimized compounds, initiate preclinical studies in our genetically engineered mouse models of lung cancer. If effective in treating tumours in this context, we will aim to move to a clinical setting. Further, we plan to use TPP to identify the molecular targets of other chemicals we have identified and work on in the lab.
If you’d like to mention your funding sources, please list them.
BC Cancer Foundation, the Cancer Research Society, Canadian Institutes of Health Research and the Terry Fox Research Institute
