BUSCADOR RECOLECTA

Drug combinations are key to circumvent resistance mechanisms compromising response to single anti-cancer targeted therapies. The implementation of combinatorial approaches involving MEK1/2 or KRASG12C inhibitors in the context of KRAS-mutated lung cancers focuses fundamentally on targeting KRAS proximal activators or effectors. However, the antitumor effect is highly determined by compensatory mechanisms arising in defined cell types or tumor subgroups. A potential strategy to find drug combinations targeting a larger fraction of KRAS-mutated lung cancers may capitalize on the common, distal gene expression output elicited by oncogenic KRAS. By integrating a signature-driven drug repurposing approach with a pairwise pharmacological screen, here we show synergistic drug combinations consisting of multi-tyrosine kinase PKC inhibitors together with MEK1/2 or KRASG12C inhibitors. Such combinations elicit a cytotoxic response in both in vitro and in vivo models, which in part involves inhibition of the PKC inhibitor target AURKB. Proteome profiling links dysregulation of MYC expression to the effect of both PKC inhibitor-based drug combinations. Furthermore, MYC overexpression appears as a resistance mechanism to MEK1/2 and KRASG12C inhibitors. Our study provides a rational framework for selecting drugs entering combinatorial strategies and unveils MEK1/2- and KRASG12C-based therapies for lung cancer., M.R. was supported by a fellowship
from MICIU (FPU15/00173). The Proteomics Platforms of Navarrabiomed led by E.S.
and J.F.-I. is a member of Proteored, PRB3 and is supported by grant
PT17/0019 of the PE I + D + i 2013¿2016, funded by ISCIII and ERDF. E.J.-L.
was supported by Foundation of Spanish Association Against Cancer
(PROYE18012ROSE), by Centro de Investigación Biomédica en Red
(CIBERONC; CB16-12-00350), and by Generalitat Valenciana (AICO/
2021/333). F.L. was funded by the Gobierno de Navarra (Ref. 34/2021),
the Cancer Research Thematic Network of the Instituto de Salud Carlos
III (RTICC RD12/0036/0066), PID2021-122638OB-I00 MCIN/AEI/
10.13039/501100011033/ FEDER, UE and by FEDER ¿Una manera de
hacer Europa¿. I.F. was funded by FIS PI19/00320 and by the Miguel
Servet Program CP21/00052. S.V. was supported by Ministerio de
Ciencia, Innovación y Universidades, Convocatoria 2019 para incentivar
la Incorporación Estable de Doctores (IED2019-001007-I), by FEDER
/Ministerio de Ciencia, Innovación y Universidades - Agencia Estatal de
Investigación (SAF2017-89944-R and PID2020¿116344¿RB¿100/MCIN/
AEI/10.13039/501100011033, by a Leonardo Grant for Researchers and
Cultural Creators 2018 from BBVA Foundation, by a seed grant at the I
Convocatoria Proyectos Prueba de Concepto from PRB3-Proteored
(Institute of Health Carlos III-ISCIII), by Fundació La Marató de TV3 (474/
C/2019), and by Foundation of Spanish Association Against Cancer -
Strategic Projects 2020 (PROYE20029VICE). M.P.-S. and S.V. were
also funded by Fundación Alberto Palatchi.

Circulating tumor cells are the key link between a primary tumor and distant metastases, but once in the
bloodstream, loss of adhesion induces cell death. To identify the mechanisms relevant for melanoma circulating
tumor cell survival, we performed RNA sequencing and discovered that detached melanoma cells and isolated
melanoma circulating tumor cells rewire lipid metabolism by upregulating fatty acid (FA) transport and FA betaoxidation‒related genes. In patients with melanoma, high expression of FA transporters and FA beta-oxidation
enzymes significantly correlates with reduced progression-free and overall survival. Among the highest
expressed regulators in melanoma circulating tumor cells were the carnitine transferases carnitine O-octanoyltransferase and carnitine acetyltransferase, which control the shuttle of peroxisome-derived medium-chain FAs
toward mitochondria to fuel mitochondrial FA beta-oxidation. Knockdown of carnitine O-octanoyltransferase or
carnitine acetyltransferase and short-term treatment with peroxisomal or mitochondrial FA beta-oxidation inhibitors thioridazine or ranolazine suppressed melanoma metastasis in mice. Carnitine O-octanoyltransferase
and carnitine acetyltransferase depletion could be rescued by medium-chain FA supplementation, indicating that
the peroxisomal supply of FAs is crucial for the survival of nonadherent melanoma cells. Our study identifies
targeting the FA-based cross-talk between peroxisomes and mitochondria as a potential therapeutic opportunity
to challenge melanoma progression. Moreover, the discovery of the antimetastatic activity of the Food and Drug
Administration‒approved drug ranolazine carries translational potential., This work was funded by the Instituto de Salud Carlos III-FEDER through PI16-01911 and PI19/00645 to IA. IA and IML acknowledge support through Miguel Servet II fellowships (CPII20/00011 and CPII20/00029). The Health Department of the Government of Navarra, Spain funded work through reference GºNa 71/17. SV is funded by FEDER/Ministerio de Ciencia, Innovación y Universidades - Agencia Estatal de Investigación (PID2020-116344-RB-100) and by Foundation Spanish Association Against Cancer (PROYE20029VICE). ILO is funded through a Navarrabiomed PhD studentship and the Grupo Español Multidisciplinar de Melanoma (reference Beca_GEM). FL was funded by the Cancer Research Thematic Network of the Instituto de Salud Carlos III (RTICC RD12/0036/0066, SAF2015-71606R, RTI2018-094507-B-100) financed by MCIN/AEI/10.13039/501100011033 and by FEDER. FL was also funded by the la Caixa Foundation, Caja Navarra Foundation, and the Foundation AECC. PA is a recipient of a Sara Borrell postdoctoral fellowship from the Instituto de Salud Carlos III (CD21/00137).