We recently demonstrated that ablation of RAF1 induces significant levels of tumour regression in mice bearing lung adenocarcinomas induced by KRas/Tp53 mutations. We observed similar results in mice bearing pancreatic tumours providing that RAF1 ablation is combined with elimination of the EGF Receptor. We are now attempting to translate these observations to a pharmacological scenario. Unfortunately, none of the available putative RAF1 inhibitors has shown antitumour activity in the clinic. Therefore, we decided to interrogate by genetic means the best strategy to block RAF1 activity. Unexpectedly, expression of 2 kinase dead isoforms of RAF1 failed to exhibit therapeutic activity, indicating that RAF1 does not contribute to tumour development via its kinase activity. Hence, pharmacological targeting of RAF1 will require the use of other strategies such as the use of degrons, small chemotypes capable of inducing the degradation of their target proteins.
The KRAS locus encodes 2 protein isoforms, KRAS4A and KRAS4B, which differ in intracellular trafficking and location in the plasma membrane. KRAS mutations in human cancer affect both protein isoforms. Efforts to selectively target the KRAS4B isoform are under development. We have observed that expression of the endogenous KRAS4A mutant oncoprotein is sufficient to induce lung adenocarcinomas. Hence, effective therapeutic strategies against KRAS mutant tumours must take into account inhibition of both protein isoforms.
Publications
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García-Alonso S, Mesa P, Ovejero LP, Aizpurua G, Lechuga CG, Zarzuela E, Santiveri CM, Sanclemente M, Muñoz J, Musteanu M, Campos-Olivas R, Martínez-Torrecuadrada J, Barbacid M, Montoya G. (2022).Structure of the RAF1-HSP90-CDC37 complex reveals the basis of RAF1 regulation. Mol Cell 82, 3438-3452. CNIO Publication.
Köhler J, Zhao Y, Li J, Gokhale PC, Tiv HL, Knott AR, Wilkens MK, Soroko KM, Lin M, Ambrogio C, Musteanu M, Ogino A, Choi J, Bahcall M, Bertram AA, Chambers ES, Paweletz CP, Bhagwat SV, Manro JR, Tiu RV, Jänne PA (2021).ERK inhibitor LY3214996-based treatment strategies for RAS-driven lung cancer.. Mol Cancer Ther 20, 641-654. CNIO Publication.
Nokin MJ, Darbo E, Travert C, Drogat B, Lacouture A, San José S, Cabrera N, Turcq B, Prouzet-Mauleon V, Falcone M, Villanueva A, Wang H, Herfs M, Mosteiro M, Jänne PA, Pujol JL, Maraver A, Barbacid M, Nadal E, Santamaría D, Ambrogio C (2020).Inhibition of DDR1 enhances in vivo chemosensitivity in KRAS-mutant lung adenocarcinoma. JCI Insight 5, 137869. CNIO Publication.
Blasco MT, Navas C, Martín-Serrano G, Graña-Castro O, Lechuga CG, Martín-Díaz L, Djurec M, Li Jing, Morales-Cacho L, Esteban-Burgos L, Perales-Patón J, Bousquet-Mur E, Castellano E, Jacob Harrys KC, Cabras L, Mustenau M, Drosten M, Ortega S, Mulero F, Sainz B, Dusetti N, Iovanna J, Sánchez-Bueno F, Hidalgo M, Khiabanian H, Hidalgo M, Rabadán R, Al-Shahrour F, Guerra C, Barbacid M (2019).Complete Regression of Advanced Pancreatic Ductal Adenocarcinomas upon Combined Inhibition of EGFR and C-RAF. Cancer Cell 35, 573-587. CNIO Publication.
Y. Gao, M. Chang, D. McKay, N. Na, B. Zhou, R. Yaeger, N. Torres, K. Muniz, M. Drosten, M. Barbacid, G. Caponigro, D. Stuart, H. Möbitz, D. Solit, O. Abdel-Wahab, B. Taylor, Z. Yao, and N. Rosen (2018).Allele-specific mechanisms of activation of MEK1 mutants determine their properties. Cancer Discovery 8, 648-651. CNIO Publication.
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