Notebook: SHP2 is required for growth of KRAS-mutant non-small-cell lung cancer in vivo

Recently Dr. Mainardi S, et al. found SHP2 is required for growth of KRAS-mutant non-small-cell lung cancer. Research published at Nature Medicine on May 28, 2018.

Lung cancer is the most common cause of cancer death worldwide, about 1.6 million deaths every year. Non-small cell lung cancer (NSCLC) is the primary type of lung cancer and occupied around 85%,and about 30% of NSCLCs have mutations in KRAS. RAS mutations are frequent in human cancer, especially in pancreatic, colorectal and non-small-cell lung cancers (NSCLCs). It is also well known that KRAS-mutant tumors are insensitive to inhibition of upstream growth factor receptor signaling. Thus, epidermal growth factor receptor (EGFR) antibody therapy is only effective in KRAS wild-type colon cancers. Consistently,inhibition of SHP2, which links receptor tyrosine kinase signaling to the RAS–RAF–MEK–ERK pathway, was shown to be ineffective in KRAS-mutant or BRAF-mutant cancer cell lines. 

Firstly, this research data suggested that a feedback loop involving RTKs is activated upon MEK inhibition. The increased RTK signaling subsequently activates the RAS–MEK–ERK pathway through SHP2 to the extent that the MEK inhibitor is unable to completely block signaling to ERK, thereby maintaining proliferation. Next, the authorsexplored the possibility of increasing sensitivity to MEK inhibition by concomitantly inhibiting RTK signaling to RAS–RAF–MEK by using a SHP2 inhibitor. It was found that SHP2 inhibition is synthetic lethal with MEK inhibition in KRAS-mutant tumors of different origins. Interestingly,the most obvious effect was observed in NSCLC.

Next,the authors conducteda series of studies in vitro and in vivo. The data indicated that SHP2 inhibition in KRAS-mutant NSCLC cells under normal cell culture conditions had little effect, but SHP2 inhibition under growth factor–limiting conditions in vitro results in a senescence response. In vivo, the availability of growth factors and other signaling molecules could be limiting, inhibition of SHP2 in KRAS-mutant NSCLC also provoked a senescence response, which is exacerbated by MEK inhibition. 

In a word, this researchsuggestedthat genetic or pharmacological inactivation of the SHP2 phosphatase in KRAS-mutant tumors could interfere with RAS signaling to the downstream MAPK signaling cascade. SHP2 inhibition alone could be sufficient, at least in some contexts, to induce tumor senescence, which in turn can trigger clearance of the cancer cells by the immune system. That data and those of Ruess et al. indicated that co-treatment with MEK inhibition might further enhance the effect of SHP2 inhibition.In short, this study showed that inhibition of SHP2 could have clinical utility for KRAS-mutant NSCLC.