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Abstract
Despite a therapeutic paradigm shift into targeted-driven medicinal approaches, resistance to therapy remains a hallmark of lung cancer, driven by biological and molecular diversity. Using genomic and expression data from advanced non-small cell lung cancer (NSCLC) patients enrolled in the BATTLE-2 clinical trial, we identified RICTOR alterations in a subset of lung adenocarcinomas and found RICTOR expression to carry worse overall survival. RICTOR-altered cohort was significantly enriched in KRAS/MAPK axis mutations, suggesting a co-oncogenic driver role in these molecular settings. Using NSCLC cell lines, we showed that, distinctly in KRAS mutant backgrounds, RICTOR blockade impairs malignant properties and generates a compensatory enhanced activation of the MAPK pathway, exposing a unique therapeutic vulnerability. In vitro and in vivo concomitant pharmacologic inhibition of mTORC1/2 and MEK1/2 resulted in synergistic responses of anti-tumor effects. Our study provides evidence of a distinctive therapeutic opportunity in a subset of NSCLC carrying concomitant RICTOR/KRAS alterations.
Highlights
Despite improvement in early detection strategies and standard treatment options, nonsmall cell lung cancer (NSCLC) continues to have a poor prognosis [1, 2]
We analyzed 92 LUAD tumor biopsies obtained from BATTLE-2 chemo-refractory patients, with matching targeted genomic next-generation sequencing (NGS) and expression profiling analyses [17]
To test for a unique therapeutic vulnerability offered by the dynamic interplay between RICTOR and KRAS/MAPK axis, we evaluated the pharmacological blockade of the MEK-ERK signaling pathway alone or in combination with genetic abrogation of RICTOR, Figure 2: Compensatory MAPK signaling activation following RICTOR knockdown in KRAS mutant settings. (A) A panel of 6 RICTOR amplified and 4 non-amplified NSCLC cell lines that are KRAS wild-type or mutant were transfected with siRNAs specific for RICTOR or scrambled negative control for 72 hours and cell lysates were analyzed by Western blotting for the specified proteins. (B) H23 and H1792 cells were transfected with siRNAs specific for RICTOR, KRAS, or scrambled negative control for 72 hours and cell lysates were analyzed by Western blotting for the specified proteins
Summary
Despite improvement in early detection strategies and standard treatment options, NSCLC continues to have a poor prognosis [1, 2]. With increased knowledge of genomic aberrations, the last decade enabled development of rapid genomic profiling leading to molecular-targeted therapies blocking key oncogenic drivers and resulting in dramatic responses in selected patients [2]. Despite initial responses, these targeting agents rarely promote complete or durable antitumor effects especially in unselected patients, leading to acquired resistance mechanisms and relapse. Effective therapeutic options are still lacking for lung tumors driven by other key mutations such as oncogenic KRAS (~30%) and those with unknown oncogenic drivers [4, 5]. RICTOR’s oncogenic role has gained momentum over recent years, with reports uncovering both canonical rate limiting activity on mTORC2-AKT, and the presence of additional mTORC2independent functionalities [13,14,15,16]
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