A study conducted by researchers from the Spanish National Cancer Research Centre (Centro Nacional de Investigadores Oncológicas) (CNIO), shows that elimination of c-RAF by genetic means leads to regression of advanced KRAS-driven lung tumors in mice (Sanclemente et al., Cancer Cell, 2018). Moreover, systemic c-RAF ablation unlike elimination of the MEK1/2 or ERK1/2 kinases, another strategy used to block K-RAS oncogenic signaling, results in acceptable toxic effects. These observations suggest that selective inhibitors of c-RAF activity that do not affect MAPK may have therapeutic activity against K-RAS mutant lung tumors, a disease for which there are no selective drugs and is still treated with ineffective cytotoxic drugs.
Lung cancer, the leading cause of cancer deaths worldwide, is a complex group of diseases that encompasses two major histological tumor types: non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC). NSCLC represents 80% of all lung cancers and includes three major histological subtypes, adenocarcinoma, squamous cell carcinoma and large cell carcinoma. During the last decade, it has been possible to further sub-classify lung adenocarcinomas based on the presence of specific mutations, believed to be key drivers of the tumorigenic process. The most frequent mutations are those present in the genes encoding K-RAS (25%), EGF Receptor (15%) and the ALK receptor (5%).
The arrival of Precision Medicine to the cancer scene has made it possible to design selective drugs against EGFR and ALK mutant tumors. Drugs such as Erlotinib, Lapatinib, Afatinib, and, more recently, Osimertinib have had a significant impact on the management of this disease. Likewise, the development of Crizotininb, and more recently Alectinib for ALK mutant tumors that become resistant to Crizotinib, have also increased the overall survival of patients with this type of lung tumors.
Unfortunately, these “success stories” have not taken place with K-RAS mutant tumors. Unlike EGFR and ALK, K-RAS is not a druggable molecule. Thus, 36 years after its discovery in human tumors, there are no selective drugs to treat this type of lung adenocarcinoma. Today, patients with K-RAS mutant tumors are still treated with combinations of old cytotoxic drugs such as docetaxel, paclitaxel or platinum-based drugs. As a consequence, overall 5-year survival rates have remained at unacceptably low numbers (12-15%) during the last 30 years. Current estimates indicate that in the US alone, every year there will be 330,000 new cases of K-RAS mutant tumors which will cause more than 120,000 deaths. Thus, the lack of appropriate medicines for this tumor type represents one of the major health issues in the Western World.
In order to attempt treating K-RAS mutant lung cancer researchers from the Spanish National Cancer Research Centre (CNIO) have developed a new generation of genetically engineered mouse (GEM) models to evaluate the effect of ablating targets with potential therapeutic activity in fully developed advanced tumors. In addition, these GEM models serve to evaluate the toxic effects caused by the systemic elimination of such targets. Indeed, attempts to block K-RAS oncogenic signaling by either genetic or pharmacologic targeting of its main signaling pathway, the MAPK cascade, have proven ineffective due to unacceptable toxic effects (Blasco et al., 2011).
In their recent study published in Cancer Cell, the authors have determined that c-RAF ablation induces a significant therapeutic effect in advanced K-RAS/TRP53 lung adenocarcinomas that closely resemble those present in human patients. Interestingly, c-RAF is a member of the MAPK cascade. However, c-RAF ablation does not affect this critical signaling pathway presumably due to the compensatory activities of other members of the RAF family of kinases such as B-Raf, which are unaffected by c-RAF ablation. Whereas these results open a new avenue to treat K-RAS mutant lung tumors also present significant challenges.
First of all, it will be necessary to unveil the alternative signaling pathway(s) blocked upon c-RAF ablation since the MAPK pathway is unaffected. While there are several candidates previously identified in other studies (McCormick, 2018), their putative therapeutic activities have not been properly evaluated. Moreover, elimination of c-RAF expression by pharmacological means will not be easy in spite of current progress in the field of degron chemistry. Finally, any pharmacological approach will have to deal with selectivity issues since panRAF inhibitors will affect MAPK signaling and therefore induce unacceptable toxic effects.
Albeit challenging, these issues are not insurmountable. Results derived from ongoing studies should shed light on future pharmacological strategies that may provide benefit to patients suffering from K-RAS mutant lung cancer.
These findings are described in the article entitled c-RAF Ablation Induces Regression of Advanced Kras/Trp53 Mutant Lung Adenocarcinomas by Mechanism Independent of MAPK Signaling, recently published in the journal Cancer Cell. This work was conducted by Manuel Sanclemente, Sarah Francoz, Laura Esteban-Burgos, Emilie Bousquet-Mur, Magdolna Djurec, Pedro P. Lopez-Casas, Manuel Hidalgo, Carmen Guerra, Matthias Drosten, Monica Musteanu, and Mariano Barbacid.
References:
- M. Sanclemente, S. Francoz, L. Esteban-Burgos, E. Bousquet-Mur, P. P. Lopez-Casas, M. Hidalgo, C. Guerra, M. Drosten, M. Musteanu and M. Barbacid (2018). c-RAF Ablation Induces Regression of Advanced Kras/Trp53 Mutant Lung Adenocarcinomas by a Mechanism Independent of MAPK. Signaling. Cancer Cell. 12;33(2):217-228.
- R.B. Blasco, S. Francoz, D. Santamaría, M. Cañamero, P. Dubus, J. Charron, M. Baccarini and M. Barbacid. (2011). c-Raf, but not B-Raf, is essential for development of K-Ras oncogene driven non small cell lung carcinoma. Cancer Cell, 19: 652-663.
- F. McCormick (2018). c-Raf in KRas Mutant Cancers: A Moving Target. Cancer Cell, 12;33(2):158-159