Effective use of PI3K and MEK inhibitors to treat mutant Kras G12D and PIK3CA H1047R murine lung cancers

Abstract

Somatic mutations that activate phosphoinositide 3-kinase (PI3K) have been identified in the p110-α catalytic subunit (PIK3CA) 1. They are most frequently observed in two hotspots: the helical domain (E545K and E542K) and the kinase domain (H1047R). Although the PIK3CA mutants are transforming in vitro, their oncogenic potential has not been assessed in genetically engineered mouse models. Furthermore, clinical trials with PI3K inhibitors have recently been initiated, and it is unknown if their efficacy will be restricted to specific, genetically defined malignancies. In this study, we engineered an inducible bitransgenic mouse model that develops lung adenocarcinomas initiated and maintained by expression of p110-α H1047R. Treatment of these tumors with NVP-BEZ235, a dual pan PI3K/mTOR inhibitor in clinical development, led to marked tumor regression as shown by PET-CT, MRI and microscopic examination. In contrast, mouse lung cancers driven by mutant K-Ras did not substantially respond to single-agent NVP-BEZ235. However, when NVP-BEZ235 was combined with a MEK inhibitor, ARRY-142886, there was dramatic synergy in shrinking these K-Ras mutant cancers. These in vivo studies suggest that inhibitors of the PI3K/mTOR pathway may be active in cancers with PIK3CA mutations, and, when combined with MEK inhibitors, may effectively treat K-RAS mutated lung cancers.

Targeted genomic profiling reveals recurrent KRAS mutations and gain of chromosome 1q in mesonephric carcinomas of the female genital tract

“…When mouse models of lung cancer driven by mutant KRAS were treated with a combination of pan-PI3K, a mammalian target of rapamycin inhibitor, and an MEK inhibitor, there was marked synergy in shrinking these tumors. [40][41][42] Sensitivity to MEK inhibition has been investigated in pancreatic cancer cell lines with specific KRAS mutations showing promising therapeutic results. 43 Because 81% of mesonephric carcinomas harbor KRAS/NRAS mutations, targeted inhibitors of the RAS/MAPK pathway could potentially be useful in the treatment of mesonephric carcinoma.…”

Molecular Profiling of Patients with Colorectal Cancer and Matched Targeted Therapy in Phase I Clinical Trials

“…In preclinical models, inhibiting the PI3K pathway showed synergy with cytotoxic agents, enhancing its efficacy by potentiating apoptosis (41). In addition, dual inhibition of the RAF/MEK and PI3K/AKT/mTOR pathways seems to be required for complete abrogation of downstream effectors in RASmutant tumors (19)(20)(21). PIK3CA and PTEN mutations strongly reduce the sensitivity of RAS-mutant cells to MEK inhibitors (42).…”

“…Their study designs are based on preclinical and early clinical response data showing the potential predictive value of specific molecular aberrations. Examples include PIK3CA-activating mutations and loss of PTEN expression and benefit with PI3K pathway inhibitors (15,16), synergistic antitumor activity with combination blockade of mTOR and IGF1R signaling (17,18), RAS/RAF mutations and response to PI3K pathway inhibitors plus MEK inhibitors (19)(20)(21), BRAF mutations linked to antitumor activity of selective BRAF inhibitors (22,23), and MET hyperactivation and benefit with MET/ HGF targeting agents (24,25).…”

Molecular basis for the actions of Hsp90 inhibitors and cancer therapy

“…PI3K and MAPK kinase inhibitors are active against k-Ras G12D, PIK3CA and H1047R murine lung cancers. 67 The combined use of NVP-BEZ235 and ARR-142886, an MAPK kinase inhibitor, showed marked synergy in shrinking k-Rasmutant murine lung cancers. 67 Hsp90 has an important role in 3-phosphoinositide-dependent protein kinase-1-Akt signaling pathway.…”

“…67 The combined use of NVP-BEZ235 and ARR-142886, an MAPK kinase inhibitor, showed marked synergy in shrinking k-Rasmutant murine lung cancers. 67 Hsp90 has an important role in 3-phosphoinositide-dependent protein kinase-1-Akt signaling pathway. 68 3-Phosphoinositide-dependent protein kinase-1 binds Hsp90, and Hsp90 inhibitor causes proteasome-dependent degradation of 3-phosphoinositide-dependent protein kinase-1.…”