Few effective therapies are available for KRAS-mutant lung cancer (KMLC). To address this problem, we seek to elucidate the biological basis for KMLC growth and metastasis and to develop novel therapies on the basis of that improved understanding. Cancer cells secrete factors that promote tumor growth, matrix remodeling, angiogenesis, and inflammation, a process hereafter termed ?malignant secretion?. Therapeutic strategies to block malignant secretion have not been developed. We have identified a chromosome 1q amplicon harboring and numerous regulators of vesicle biogenesis and trafficking, including phosphatidylinositol 4-kinase III? (PI4KIII?), a Golgi-dedicated kinase that generates phosphatidylinositol 4-phosphate (PI4P). We show that the viability and proliferative and invasive activities of 1q?amplified KMLC cells require PI4KIII?. A selective PI4KIII? antagonist preferentially induced apoptosis and inhibited the metastatic properties of 1q?amplified KMLC cells. On the basis of these findings, we hypothesize that high PI4KIII? levels promote KMLC growth and metastasis and confer vulnerability to PI4KIII? antagonists. To test this hypothesis, we propose in Aim 1 to an autochthonous PI4KIII??expressing KMLC model and determine whether PI4KIII? enhances KMLC metastatic propensity and confers vulnerability to PI4KIII? antagonists. Our findings will elucidate the way in which PI4KIII? drives KMLC progression and may provide a foundation for new therapeutic approaches using PI4KIII? antagonists. We show that high PI4KIII? levels in 1q?amplified KMLC cells enhanced anterograde vesicular trafficking and stimulated the secretion of pro-survival and pro-metastatic factors. PI4KIII??driven metastatic properties required Golgi phosphoprotein 3 (GOLPH3), a PI4P?tethered Golgi protein that promotes vesicle budding from the trans-Golgi network. Therefore, we postulate that PI4KIII?-dependent secretion is required to activate pro- metastatic processes in the tumor microenvironment and maintain the viability of 1q-amplified KMLC cells. To test this hypothesis, we will inactivate Golph3 in PI4KIII?-expressing autochthonous KMLCs and 1q-amplified orthotopic KMLCs. Resultant changes in tumor cell viability and inflammatory, stromal, and vascular cell functions in the tumor microenvironment will be measured. We will identify PI4KIII?-dependent secreted proteins that mediate these changes and elucidate how they exert these functions. Our findings will provide insight into how a secretory process activated by a chromosomal region that is frequently amplified in cancer maintains tumor cell viability and influences diverse processes in the tumor microenvironment. In summary, the evidence presented here links malignant secretion to a chromosomal region that is frequently amplified in KMLC and provides a basis for clinical studies to develop PI4KIII? antagonists as first- in-class inhibitors of malignant secretion. Our findings elucidate the molecular underpinnings of malignant secretion and show that chromosome 1q-amplified cancers are vulnerable to secretory blockade.
There are few effective therapeutic options for KRAS-mutant lung cancer (KMLC), and there is an urgent need to develop a better understanding of the biological basis of KMLC growth and metastasis. On the basis of the preliminary results presented here, we postulate that KMLC growth and metastasis is driven by a chromosome 1q amplicon containing an actionable Golgi-dedicated kinase (PI4KIII?) that promotes secretion of pro- tumorigenic effector proteins. If proven true, these findings would advance our understanding of the mechanisms of KMLC progression and would provide a rationale to advance PI4KIII? antagonists into clinical trials for the treatment of KMLC and other chromosome 1q-amplified tumor types.
