Molecular Oncology Programme

Experimental Oncology Group

Group Leader:  Mariano Barbacid
Research highlights
A B-Raf kinase inactive mutant is a driver oncogene in lung adenocarcinoma

The initiating oncogenic event in almost half of human lung denocarcinomas is still unknown; a fact that complicates the development of selective targeted therapies. We have demonstrated that expression of an endogenous B-RafD631A kinase inactive isoform, present in a significant percentage of human lung tumours, triggers lung adenocarcinoma in vivo, indicating that BRAF inactivating mutations represent novel oncogenic drivers. Moreover, these BRAF mutations have also been identified in a subset of K-RAS driven human lung tumours. Co-expression of K-RasG12V and B-RafD631A mutations dramatically enhances tumour initiation, a phenomenon mediated by c-Raf kinase activity and that effectively accelerates tumour progression in advanced lung adenocarcinomas. Concomitant ablation of the wild type B-Raf allele prevents lung adenocarcinoma by inducing oncogenic toxicity. Loss of B-Raf expression in this scenario lso induces trans-differentiation of Clara cells, leading to the development of intrabronchiolar lesions that result in the rapid death of the mice. We have also shown that this class of BRAF mutants are sensitive to ERK-mediated feedback and that their ctivation of signalling is dependent on RAS activation. The dependence of these mutants on RAS suggests that their activation of ERK signalling requires incomplete feedback inhibition of RAS activation. Indeed, these are sensitive to inhibition of RAS ctivation, which can be achieved by using available inhibitors of tyrosine protein kinase receptors.

Inactivation of Capicua in adult mice causes T cell lymphoblastic lymphoma

Capicua (CIC) is a transcriptional repressor negatively regulated by RAS/MAPK signalling. CIC is inactivated in a variety of human tumours and has recently been implicated in lung metastasis. Here, we describe a mouse model in which we inactivate Cic by blocking its transcriptional repressor activity. Cic function is essential for embryonic development but not for adult homeostasis. Systemic inactivation of Cic in adult mice results in T-cell acute lymphoblastic lymphoma (T-ALL) with high penetrance. Although Cic inactivation induces a large transcriptional program, T-ALL is mediated by the selective expression of the Etv4 transcription factor. We also show that a genetic signature indicative of Cic inactivation is enriched in Ras-induced T-ALL. Indeed, Cic mutations render T-ALL insensitive to MEK inhibitors. More importantly, human T-ALL also displays this signature, indicating that CIC inactivation plays a key role in this human malignancy and may confer resistance to inhibitors of the MAPK pathway.

In vivo oncogenic conflict triggered by co-existing KRAS and EGFR activating mutations in lung adenocarcinoma

Activating mutations in KRAS and EGFR, the two most frequent oncogenic drivers in human lung adenocarcinoma, occur in a mutually exclusive manner suggesting functional redundancy and implying lack of positive selection. By means of a mouse model engineered to induce expression of mutant EGFRL858R in advanced tumours driven by a resident KrasG12V oncogene we show that, instead, their co-expression is detrimental for the progression of lung adenocarcinoma. In vivo, expression of EGFRL858R in KrasG12V-driven tumours triggers an immediate response with hallmarks of replicative stress resulting in apoptosis. Yet, a fraction of tumour cells survive but enter a transient cytostatic state incompatible with tumour development that is fully reversible upon discontinuation of EGFRL858R expression. Ultimately, continuous co-expression of both mutants results in the attenuation of the overall oncogenic signalling to levels compatible with cell proliferation and tumour growth. In sum, our results indicate that the mutual exclusivity of KRAS and EGFR activating mutations occurs as a combination of cellular toxicity and signal adjustment that results in the lack of selectivadvantage for those cells expressing both oncogenes.