Abstract
The genetic and metabolic heterogeneity of RAS-driven cancers has confounded therapeutic strategies in the clinic. To address this, rapid and genetically tractable animal models are needed that recapitulate the heterogeneity of RAS-driven cancers in vivo. Here, we generate a Drosophila melanogaster model of Ras/Lkb1 mutant carcinoma. We show that low-level expression of oncogenic Ras (RasLow) promotes the survival of Lkb1 mutant tissue, but results in autonomous cell cycle arrest and non-autonomous overgrowth of wild-type tissue. In contrast, high-level expression of oncogenic Ras (RasHigh) transforms Lkb1 mutant tissue resulting in lethal malignant tumors. Using simultaneous multiview light-sheet microcopy, we have characterized invasion phenotypes of Ras/Lkb1 tumors in living larvae. Our molecular analysis reveals sustained activation of the AMPK pathway in malignant Ras/Lkb1 tumors, and demonstrate the genetic and pharmacologic dependence of these tumors on CaMK-activated Ampk. We further show that LKB1 mutant human lung adenocarcinoma patients with high levels of oncogenic KRAS exhibit worse overall survival and increased AMPK activation. Our results suggest that high levels of oncogenic KRAS is a driving event in the malignant transformation of LKB1 mutant tissue, and uncovers a vulnerability that may be used to target this aggressive genetic subset of RAS-driven tumors.
Highlights
The genetic and metabolic heterogeneity of RAS-driven cancers has confounded therapeutic strategies in the clinic
We found that activation of CamkIIB was elevated in Ras at levels several-fold higher (RasHigh)/Lkb1−/− tumors (Fig. 5a and Supplementary Fig. 5), suggesting a conserved role for this kinase in activating Ampk in the presence of oncogenic Ras tumors lacking Lkb[1]
We found no difference in overall survival in KRASLow/LKB1Mut vs. KRASLow patients (HR 2.181 95% CI, 0.9136–5.205), but strikingly KRASHigh/LKB1Mut patients exhibited significantly worse overall survival when compared with RASHigh patients (HR 2.72; 95% CI, 1.132–6.546) (Fig. 6a, b)
Summary
The genetic and metabolic heterogeneity of RAS-driven cancers has confounded therapeutic strategies in the clinic. Loss of LKB1 frequently occurs in KRAS-driven lung adenocarcinoma, and has been shown to promote metastasis, shorten overall survival, and confer resistance to targeted therapies and checkpoint inhibitors[6,7,8,9,10] These differences in survival and treatment outcomes highlight the importance of in vivo models that recapitulate the complexity and heterogeneity of these tumors when developing and implementing cancer treatments. Elegant genetic mosaic techniques in Drosophila allow tissue-specific overexpression of oncogenes and knockdown of tumor suppressors within distinct subpopulations of cells, which bestows the ability to build complex tumor landscapes in vivo Seminal work using these methods has identified cooperating mutations that promote the metastasis of benign Kras-mutant tumors in vivo, and has identified such cooperating models as amenable to pharmacologic approaches[13,14,15,16]. Our work proves Drosophila as a powerful model for the rational design of targeted therapies for genetic subsets of RASdriven cancers, and suggests that the LKB1 subset of KRASdriven cancers may benefit from targeting of the CAMKK/AMPK circuit
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