This week we profile a recent publication in npj Precision Oncology from the lab of Dr. William Lockwood (pictured, far right) with first author Dylan Farnsworth (second from right) at BC Cancer.
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 study builds on our previous work demonstrating that too much oncogenic signaling is lethal for lung cancer cells. This is a counterintuitive concept, as one would think that more signaling would yield more aggressive cancers. However, our work using multiple systems has shown that engineering lung cancer cells to amplify the commonly mutated EGFR-RAS-MAPK signaling axis leads to cell death. We have since been working on how this concept could be exploited for patient care. In this paper, we made KRAS mutant lung cancer cells resistant to a targeted therapy that blocks MAPK signaling. We found that some of these resistant cells became addicted to the treatment for the drug to survive; they grow fine when drug is present, but when removed, the cancer cells died. This was unexpected, and we subsequently found that these cells died due to too much oncogenic signaling after drug withdrawal. Genomic profiling revealed that these cells acquired mutant KRAS amplification, which drove their resistance to the drug, but also made them susceptible to cell death upon drug removal. We later found that mutant KRAS amplification can drive cell death, confirming these findings. Importantly, we found that in some lung cancer patients treated with mutant KRAS inhibitors, drug resistance occurred after KRAS amplification, suggesting that these findings could be relevant to the clinical setting.
What are the next steps for this research?
This study opens up many new areas of investigation for our group. One main question is whether specific patients that become resistant to targeted therapies may benefit from a “drug holiday”. Essentially, the idea is that in patients with KRAS amplification, drug removal should lead to tumor regression. The idea is to screen for these specific patients and test this concept in the clinic. Furthermore, we want to see if this “drug addiction” phenotype occurs with other targeted agents used for lung cancer patients and whether we can combine drug withdrawal with treatment with other agents that hyperactivate oncogenic signaling to further increase tumor regression.
If you’d like to mention your funding sources, please list them.
Our work wouldn’t be possible without a program project grant from the Canadian Institutes of Health Research and funding for our students, including a Rising Star Award to lead author Dylan Farnsworth from the BC Cancer Foundation.
