Lkb1inactivation is sufficient to drive endometrial cancers that are aggressive yet highly responsive to mTOR inhibitor monotherapy

Abstract

SUMMARYEndometrial cancer -the most common malignancy of the female reproductive tract -arises from the specialized epithelial cells that line the inner surface of the uterus. Although significant advances have been made in our understanding of this disease in recent years, one significant limitation has been the lack of a diverse genetic toolkit for the generation of mouse models. We identified a novel endometrial-specific gene, Sprr2f, and developed a Sprr2f-Cre transgene for conditional gene targeting within endometrial epithelium. We then used this tool to generate a completely penetrant Lkb1 (also known as Stk11)-based mouse model of invasive endometrial cancer. Strikingly, female mice with homozygous endometrial Lkb1 inactivation did not harbor discrete endometrial neoplasms, but instead underwent diffuse malignant transformation of their entire endometrium with rapid extrauterine spread and death, suggesting that Lkb1 inactivation was sufficient to promote the development of invasive endometrial cancer. Mice with heterozygous endometrial Lkb1 inactivation only rarely developed tumors, which were focal and arose with much longer latency, arguing against the idea -suggested by some prior studies -that Lkb1 is a haploinsufficient tumor suppressor. Lastly, the finding that endometrial cancer cell lines were especially sensitive to the mTOR (mammalian target of rapamycin) inhibitor rapamycin prompted us to test its efficacy against Lkb1-driven endometrial cancers. Rapamycin monotherapy not only greatly slowed disease progression, but also led to striking regression of pre-existing tumors. These studies demonstrate that Lkb1 is a uniquely potent endometrial tumor suppressor, but also suggest that the clinical responses of some types of invasive cancers to mTOR inhibitors may be linked to Lkb1 status.

Germinal center kinases in immune regulation

“…As a major upstream regulator of AMPactivated protein kinase subfamily members, including MARK/Par-1, LKB1 is involved in multiple aspects of cell function and has been linked to many human diseases especially malignant tumors. [63][64][65][66][67][68][69][70][71] Recently, LKB1 has been implicated in B-cell differentiation by mediating activation-induced cytidine deaminase-dependent remodeling of immunoglobulin genes, 72 as well as in T-cell differentiation by regulating TCR-mediated activation of phospholipase C gamma1 and AMP-activated protein kinase signaling. 73,74 LKB1 is directly phosphorylated by lymphocyte-specific protein tyrosine kinase and predominantly interacts with the adaptor protein LAT as well as phospholipase C gamma1 following TCR stimulation.…”

LKB1-AMPK axis revisited

“…LKB1 is an established tumor suppressor that is mutationally inactivated in a wide variety of epithelial cancers and promotes tumorigenesis when deleted in mouse models. While the underlying mechanisms for LKB1-mediated tumor suppression are not fully defined, the key role of AMPK in inactivating mTOR is thought to contribute to this process [1,2] .…”

“…This tumor suppressive function may involve the ability of the LKB1-AMPK pathway to promote mTOR inactivation by TSC2 and raptor phosphorylation [1,2], as well as functions of other members of the family of AMPK-related kinases.…”

LKB1 gene inactivation does not sensitize non-small cell lung cancer cells to mTOR inhibitors in vitro

“…Shackelford found that rapamycin monotherapy decreased polyp burden and size in LKB1 +/-mice with polyposis [18] . In addition, endometrial cancers with LKB1 inactivation are highly responsive to mTOR inhibitors [11] , which led us to speculate that LKB1 may be a predictor of response to rapalogs. However, in the present study, we found that NSCLC cells are insensitive to rapamycin or RAD001 by both MTS and SRB assays, and the cellular response to mTOR inhibitors has no association with LKB1 gene status.…”

“…Accordingly, LKB1-inactivated endometrial cancers have been shown to be highly responsive to mTOR inhibition [11] . Therefore, LKB1 deficiency in tumors appears to be a predictive for good clinical responses to mTOR inhibitors.…”