Lung cancer is the leading cause of cancer mortality worldwide with a five-year survival rate of ~10 to 15%. Non-small cell lung carcinoma (NSCLC) accounts for ~80% of all lung cancer cases, and can be divided in distinct subtypes including adenocarcinoma, squamous cell carcinoma (SCC), and large cell carcinoma (LCC). Major drivers of lung adenocarcinoma include mutations in KRAS (~30%) and EGFR (15%), while amplification of receptor tyrosine kinases (RTKs) and loss of tumor suppressors has been linked to SCC. However, the identities of the pathways that promote the progression of ~40% of adenocarcinoma, ~60% of SCC, and the majority of LCC tumors, are currently unknown. Moreover, current therapies against EGFR and other `driver' kinases have shown to be ineffective due to variable, transient and incomplete responses. Thus, progression of lung tumors may require the activity of downstream kinases required for the regulation of tumor growth, survival and/or metastasis. Based on our recent findings we propose that candidates for such kinases are the Abl non-receptor kinases. We found that Abl kinases are up-regulated in subsets of primary human lung tumors, and demonstrate that inhibition of Abl kinases markedly impairs the growth of selected NSCLC subtypes, as well as Kras-driven lung tumors in mice. Moreover, we uncovered an essential role for Abl kinases in promoting metastases of KRAS and EGFR mutant lung cancer cells. Further, we found that inhibition of Abl kinases sensitized selected therapy-resistant lung cancer cells to targeted therapies. Our central hypotheses are that Abl kinases promote lung tumor progression and metastasis, and that inhibition of Abl kinases might be exploited for treating selected lung tumors. To test these hypotheses we propose the following specific aims: 1) Define the mechanisms by which Abl kinases promote metastasis of lung cancer cells, and evaluate the effectiveness of novel Abl kinase inhibitors in treating NSCLC metastasis. 2) Define the role of Abl family kinases in lung tumor progression using genetically engineered autochthonous Kras-driven lung cancer mouse models and pharmacological inhibition or genetic inactivation of Abl kinases. 3) Evaluate whether inhibition of the Abl kinases sensitizes selected therapy-refractory tumors to growth inhibition by targeted chemotherapies, and dissect the mechanism underlying this response. Results from this proposal will yield novel insights into the signaling networks regulated by Abl kinases in selected lung cancer cells. Further, the availability of new specific Abl kinase inhibitors as well as mouse models with conditional deletion of the Abl kinases generated in our laboratory will allow for rapid evaluation of these kinases as targets for the treatment of therapy-refractory lung cancer.
Results from these studies are expected to identify signaling networks in lung tumors regulated by the Abl family kinases during tumor progression and metastasis, and will identify combination therapies that function in concert with inactivation of the Abl kinases to inhibit the growth of selected and difficult to treat lung cancer subtypes. The proposed studies are likely to generate new combination therapies for treatment of therapy-refractory lung tumors.
| Gu, Jing Jin; Rouse, Clay; Xu, Xia et al. (2016) Inactivation of ABL kinases suppresses non-small cell lung cancer metastasis. JCI Insight 1:e89647 |
| Khatri, Aaditya; Wang, Jun; Pendergast, Ann Marie (2016) Multifunctional Abl kinases in health and disease. J Cell Sci 129:9-16 |
| Matsumoto, Yoshinori; La Rose, Jose; Kent, Oliver A et al. (2016) Reciprocal stabilization of ABL and TAZ regulates osteoblastogenesis through transcription factor RUNX2. J Clin Invest 126:4482-4496 |
