Activation of PI3K/AKT pathway is one of the most recurrent resistant mechanisms for BRAF-targeted therapy, and the combination of MAPK and PI3K/AKT inhibitors becomes one of the most promising regimens for BRAF-targeted relapsed melanoma patients. Although the potent drug efficacy was observed in preclinical experiments and early clinical trials, the dual-drug resistance is inevitable observed. Herein, researchers reported systematically study on the mechanisms of dual-drug resistance to MAPKi and PI3K/mTORi in melanoma.

Targeting BRAFV600E with small molecules in metastatic melanoma has been shown promising outcomes in preclinical experiments and clinical trials. There are two main aspects of the molecular mechanisms for drug resistance of targeted BRAFV600E therapy. One is reactivation of MAPK pathway. The other is the activation of alternative survival networks, the majority of which involved in PI3K/AKT pathway.

Several clinical trials have been initiated to evaluate the safety and effects of combination therapy with MAPKi and PI3K/mTORi in melanoma patients. However, though combination targeted therapies show prosperous prospects for the treatment of metastatic melanoma, the development of drug resistance is still inevitable with times (Fig. 1). Further investigation is urgently needed in advance to elucidate the molecular mechanisms of dual-drug resistance.

In this study, researchers aimesd to investigate the compensatory pathway of dual-drug resistance and seek for a potential novel combinatorial regimen for overcoming tumor relapse. With transcriptomic dissection of dual-drug resistant models, we identified that the drug tolerance was mediated by ECM-integrins α3β1 and α11β1 signaling. Upon binding ECM, the integrins activated downstream kinase Src rather than FAK, WNT, or TGFβ. Knockdown of integrins α3, α11, and β1 significantly inhibited the proliferation of dual-drug resistant sublines while with trivial effects on parental cells. Although Src inhibition suppressed the phosphorylation of AKT, c-JUN, and p38, none of inhibitors targeting these kinases reversed the dual-drug resistance in model cells. Notably, Src inhibitor promoted the phosphorylations of LATS1 and YAP1, subsequently, re-localized YAP1 from nucleus to cytosol facilitating further degradation. Both small molecule inhibitors and shRNAs targeting YAP1 or Src overcame the MAPKi and PI3K/mTORi dual-drug resistance. In conclusion, our data not only illuminated an integrin-Src-YAP1 pathway mediated MAPKi and PI3K/mTORi dual-drug resistant mechanism but also provided a potential combinatorial regimen for the drug-relapsed melanoma patients.

Fig. 1 Chronic MAPK and PI3K dual-inhibition lead to acquired drug resistance

Article Access: https://link.springer.com/article/10.1186/s43556-020-00013-0

Website for Molecular Biomedicine: https://www.springer.com/journal/43556

Looking forward to your contributions