Elucidating the Roles of the RAS-Regulated MAPK and PI3K Pathways and Autophagy Signaling in Lung Cancer

• Main Author: Ghazi, Phaedra C
• Format: Dissertation
• Language: English
• Published: ProQuest Dissertations & Theses 01-01-2024
• Subjects: Cellular biology; Genetics; Molecular biology; Oncology
• ISBN: 9798384099420

Lung cancer is the deadliest type of cancer both in the USA and worldwide. The most common type of lung cancer is lung adenocarcinoma, which originates from alveolar epithelial cells in the lung. Within lung adenocarcinoma, many different molecular drivers influence disease progression and treatment strategies. Mutational activation of KRAS is the most frequent oncogenic driver in lung adenocarcinoma. For many decades, with multiple failed attempts, there was no targeted therapy available for patients with KRAS mutant lung cancer. Within the last 10 years, the ability to directly target KRAS with a small molecule inhibitor has greatly improved. Although many patients harboring KRASG12C mutations in their lung tumors do respond favorably to KRASG12C inhibition, it was demonstrated that patients can quickly acquire resistance or not respond innately. Therefore, additional treatment strategies are needed to offer patients the deepest and most durable response. We have previously demonstrated that RAS-driven cancer cells treated with a MEK1/2 inhibitor upregulate a nutrient scavenging pathway, autophagy, to survive during targeted therapy treatment. Co-targeting downstream RAS signaling with a MEK1/2 inhibitor trametinib in combination with a lysosomal inhibitor hydroxychloroquine led to increased responses in models of RAS-driven pancreatic cancer. Recently, a novel selective autophagy inhibitor, DCC-3116, became available to directly target ULK1/2, a master regulator of autophagy. Therefore, we set out to determine if KRASG12C mutant lung cancer cells increased autophagy after KRASG12C inhibition, and if so, can we combine sotorasib with DCC-3116 to decrease cellular proliferation and tumor growth. In addition to mutationally activated KRAS, activation of PI3K and AKT can contribute to lung tumorigenesis. However, most research testing the effects of activated AKT on lung tumorigenesis is done with additional activation of PI3K either through a point mutation in PI3K itself, or loss of PTEN expression. Therefore, it is unclear to what extent activation of AKT cooperates with other oncogenic drivers of lung tumorigenesis independent of activation of PI3K or loss of PTEN expression. Because AKT can regulate autophagy signaling, we also set out to test what extent pharmacological inhibition of AKT and PI3K influence autophagy levels in the cell.