Johnathan Whetstine, PhD

Lung cancer is the leading cause of cancer-related deaths in the U.S. Aberrant duplication of the genome contributes to a diverse population of cancer cells within lung tumors and increases lung cancer-associated risk and drug resistance. Identifying factors and mechanisms influencing genome stability and drug resistance will impact our ability to treat lung cancer. We discovered multiple enzymes that lead to localized variations in the number of DNA copies in regions linked to drug-resistant lung cancer. We will investigate the molecular details that these enzymes are controlling in order to generate variations in the number of copies of a particular gene, while establishing the impact that additional biological pathways have on cancer gene amplification (copies) in lung cancer. Our research will uncover novel biomarkers in lung cancer and identify unappreciated drug targets to control tumor diversity and resistant lung cancer. 

Update: Aberrant DNA replication and copy generation of the genome contribute to lung tumor heterogeneity, increased cancer-associated risk and drug resistance. For example, DNA amplification and heterogeneity in lung cancer impacts oncogenes and the associated therapeutic response. Our laboratory is determining how replication control and gene amplification is impacting lung cancer-associated copy gains, while aiming to control these events and their associated therapeutic response. These data will identify drug targets for treating DNA amplification and drug resistance. In the past year, we significantly advanced our understanding about how genome replication and amplification occur, while establishing paths to explore in upcoming years.

Enzyme Could Help Predict Effectiveness of Lung Cancer Chemotherapy (2021-2022)

The COVID-19 pandemic has been an unprecedented time in the history of the world. During this time, research came to a halt across the globe, including our laboratory, but research started to return back to a more standard pace. While we have begun to ramp up to our standard pace, our lab team has been very excited about being able to tackle the questions we have set out to understand. We have used a number of adapted tools since the pandemic to help fuel our lab communication and progress. For example, zoom and other communication platforms allow us to meet with collaborators more frequently and to maintain visual discussions with one another as COVID exposure or class schedules influence in-person interactions. The pandemic trained us how to interact in a more effective manner. During the pandemic, I have also managed to give virtual presentations and seminars that have furthered the knowledge in the scientific community. These forums are also allowing us to impact a broader audience and highlight our discoveries that have been funded by ALA to a wider range of individuals. For example, I have given keynote addresses at scientific venues as well as spoke to advocacy groups for lung cancer. These interactions have also resulted in us being able to meet more patients and survivors so they can learn more about research. In fact, we have hosted several to our laboratory since the pandemic has started to be more manageable. I also delivered an opening address to the Philadelphia Lung Force Walk in 2021 and co-lead a team for 2021 and again in 2022. We also organized a lung cancer awareness event late last summer that included patients, researchers, trainees, clinicians and other people within the community, including a former NFL football player. These experiences have allowed my trainees to become advocates for research and to be reminded of the importance of conducting research. In addition to talks, I have also worked with trainees to write and publish four manuscripts that ALA funds helped support. Our studies have also resulted in us being commissioned to write three reviews for the end of 2022 and 2023. Lastly, I have been working with industry partners during this time to establish collaborative opportunities for the lab and within the cancer epigenetics institute and research program so that trials and associated collaborative research can be initiated. These efforts have resulted in such a combination that will include small cell lung cancer as a target later in 2022. In closing, we are more effective in communication and delivering a research message to both the scientific and lay communities. We have been able to advance our projects and publish our findings, while expanding the impact of our studies within the community. Funding from ALA has been instrumental in our success and ability to develop methods and hypotheses that are addressing the key question of resistance and heterogeneity in lung cancer. We are looking forward to conducting additional studies and disseminating information through the continued support of the ALA.

Mini Update: Aberrant DNA replication and copy generation of the genome contribute to lung tumor heterogeneity, increased cancer-associated risk and drug resistance. For example, DNA amplification and heterogeneity in lung cancer impacts oncogenes and the associated therapeutic response. Our laboratory is determining how replication control and gene amplification is impacting lung cancer-associated copy gains, while aiming to control these events and their associated therapeutic response. These data will identify drug targets for treating DNA amplification and drug resistance. In the past year, we significantly advanced our understanding about how genome replication and amplification occur, while establishing paths to explore in upcoming years.

Impact Statement: The American Lung Association Lung Cancer Discovery award provides us the resources to explore our discoveries in lung cancer. Without this support, our research program would be greatly hindered. This award also provides our research team an opportunity to communicate with the public and to advocate for lung cancer research, which is very gratifying and helps spread the news about the importance of research.