title: Adaptive resistance to targeted therapies in cancer.
abstract: It is widely acknowledged that there is a need for molecular profiling in non-small-cell lung cancer. For example, treatment based on EGFR mutation status has attained successful results. However, in spite of excellent initial response to oral EGFR tyrosine kinase inhibitors (TKIs), progression-free survival is still limited. Current research has focused mostly on acquired resistance mechanisms, such as overexpression of AXL and loss of the Mediator MED12. In this review, in contrast, we discuss adaptive, rather than acquired, resistance. Adaptive resistance can occur almost immediately after starting targeted therapy through a rapid rewiring of cancer cell signaling. By losing ERK negative feedback on receptor tyrosine kinase (RTK) expression, cancer cells are exposed to the stimuli of several ligands, and the ensuing activation of several RTKs reprograms all the canonical signaling pathways. The overexpression of several RTKs was observed in breast cancer cell lines treated with a MEK inhibitor and in BRAF(V600E) melanoma cell lines treated with BRAF inhibitors. This rebound effect of overexpression of several RTKs, including ERBB3, also occurs in lung cancers driven by Kras or EGFR mutations when treated with MEK, PI3K or dual PI3K/mTOR inhibitors. Synthetic lethality can be effectively induced by co-targeting these overexpressed RTKs. We speculate that in patients with EGFR mutations, adaptive resistance occurs in a significant proportion of patients. Rebiopsies performed hours after starting treatment with EGFR TKIs can identify which RTKs are overexpressed after treatment. Efficient co-targeting of these RTKs can induce synthetic lethality and help overcome the limited effect of EGFR TKI monotherapy.
authors: Catalan Institute of Oncology, Hospital Germans Trias i Pujol, Badalona, Spain ; ; Pangaea Biotech, Dexeus University Institute, Barcelona, Spain ;
authors: Rafael
authors: R
authors: Rosell
authors: Pangaea Biotech, Dexeus University Institute, Barcelona, Spain ;
authors: Niki
authors: N
authors: Karachaliou
authors: Hospital Medica Sur, Mexico DF, Mexico ;
authors: Daniela
authors: D
authors: Morales-Espinosa
authors: Pangaea Biotech, Dexeus University Institute, Barcelona, Spain ;
authors: Carlota
authors: C
authors: Costa
authors: Pangaea Biotech, Dexeus University Institute, Barcelona, Spain ;
authors: Miguel Angel
authors: MA
authors: Molina
authors: Pangaea Biotech, Dexeus University Institute, Barcelona, Spain ; ; Hospital Vall Hebron, Barcelona, Spain ;
authors: Irene
authors: I
authors: Sansano
authors: IOR, Dexeus University Institute, Barcelona, Spain ;
authors: Amaya
authors: A
authors: Gasco
authors: IOR, Dexeus University Institute, Barcelona, Spain ;
authors: Santiago
authors: S
authors: Viteri
authors: Hospital General de Alicante, Spain ;
authors: Bartomeu
authors: B
authors: Massuti
authors: The Comprehensive Cancer Center of Drum Tower Hospital, Nanjing, China.
authors: Jia
authors: J
authors: Wei
authors: IOR, Dexeus University Institute, Barcelona, Spain ;
authors: María
authors: M
authors: González Cao
authors: IOR, Dexeus University Institute, Barcelona, Spain ;
authors: Alejandro
authors: A
authors: Martínez Bueno
keywords: Adaptive resistance; RTK reprogramming; signalability; synthetic lethality