August 2015, Vol 4, No 4

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Molecular Pathways in Cancer Are Increasingly Being Exploited

Mechanism of Action/Pathway Profiles

Molecular pathways in cancer can be exploited for therapy, and sensitizing genetic aberrations are the ideal targets, said Alex Adjei, MD, PhD, at PMO Live 2015.

Cancer cells have to evade a number of stresses to grow. They are complex and live in a toxic environment, but somehow they manage to survive.

All the cancer driver genes can be classified into 1 or more of 12 signaling pathways thought to confer a selective growth advantage. These pathways can themselves be further organized into 3 core cellular processes (cell survival, cell fate, and genome maintenance). Multiple agents currently in the clinic attack most of these pathways.

The RAS-RAF-MEK-ERK pathway is an important MAP kinase pathway that is evolutionally conserved across species. It is activated by a variety of growth factors and cytokines, including epidermal growth factor, insulin-like growth factor, and transforming growth factor. These growth factors activate RAS through conversion of the inactive guanosine diphosphate–bound form to the active guanosine triphosphate–bound form. Activated RAS recruits RAF kinase to the membrane, where it is activated by phosphorylation, which in turn phosphorylates and activates MEK kinase. MEK kinase phosphorylates and activates ERK kinase; phosphorylated ERK can translocate to the nucleus and phosphorylate and activate transcription factors.

Aberrant activation of the RAS-RAF-MEK-ERK pathway occurs in more than 30% of human cancers. “Over the last 10 or 15 years, we have really tried to target all aspects of this pathway,” said Adjei, Professor and Chair, Department of Medicine, Roswell Park Cancer Institute, Buffalo, NY. In particular, MEK1/2 inhibitors appeared to be an attractive therapeutic strategy targeting this pathway.

However, “if you looked at most of these agents in most of our solid tumors, they haven’t worked very well,” he said. “We get a few responses in selected cases, but if you think about what we thought about these pathways, and their importance in cancer, and the excitement when these agents came to the clinic, they haven’t turned out to be so.” Part of the reason is the crosstalk between pathways that promotes activation of other pathways via a feedback loop.

What accounts for the lack of strong therapeutic activity of MEK inhibitors in early-stage clinical trials? Feedback inhibition of ERK on RAF is abrogated by MEK inhibitors, explained Adjei, leading to activation of MEK independent of downstream RAF targets and resistance to apoptosis. This phenomenon may explain the lack of activity of single-agent MEK inhibition in many tumors.

“We hypothesized that a MEK inhibitor should synergize with a BRAF inhibitor,” said Adjei.

BRAF mutations are observed in 2% to 3% of lung cancers, he said. More than half of the mutations are V600E hotspot mutations, and 43% are non-V600E mutations distributed in narrow areas between codons 594 and 606 on exon 15, and between 446 and 449 on exon 11.

In non–small-cell lung cancer (NSCLC), the pattern of BRAF mutations is dependent on the stage of the disease. Mutations in V600E are more abundant in advanced stages of NSCLC compared with local disease. NSCLC patients with BRAF V600E mutations have significantly worse disease-free survival and overall survival (OS) compared with wild-type disease. When considering all potential BRAF mutants, however, patients with advanced lung cancer who harbor V600 mutations have improved OS compared with non-V600 mutations.

In patients with BRAF V600E–mutant advanced NSCLC, single-agent dabrafenib is associated with an overall response rate (ORR) of 32% and is relatively well tolerated, according to phase 2 data released at ESMO 2014 (Planchard D, et al). Combining trametinib with dabrafenib increases the ORR to 63%.

Aberrations in RET

The rearranged during transfection (RET) gene resides on chromosome 10. It has a ligand called glial cell line–derived neurotrophic factor (GDNF), which has its own receptor. RET activation requires the formation of a trimeric complex that includes the ligand, a GDNF-family receptor-alpha protein, and RET.

Historically, RET aberrations have been associated with thyroid cancers. Somatic and germline point mutations occur in sporadic and familial medullary thyroid cancers, respectively. RET fusions are found in papillary thyroid cancers. The frequency of RET aberrations in unselected NSCLCs is low at about 2%, said Adjei.

Cabozantinib inhibits multiple targets, including RET, and was studied in 20 patients with advanced RET-rearranged lung cancers (ASCO 2015. Abstract 8007). Because cabozantinib is relatively toxic, 60% of patients in the study had to have dosages reduced. The best response was a partial response in 33%. Stable disease rate was 72%. The median progression-free survival was 7 months, and the median OS was not reached.

Oncogenic Mutations: Only Some Are Predictive

Not all “oncogenic” mutations are predictive biomarkers, said Adjei. PIK3CA is one mutation that was predictive of response to PIK3CA kinase inhibition in a primary human NSCLC tumor–derived xenograft. In contrast, double mutation with PIK3CA and KRAS was not sensitive. Likewise, an NSCLC tumor–derived xenograft with wild-type PIK3CA and KRAS, BRAF, and PTEN mutations was resistant to PIK3CA kinase inhibition. However, primary human breast tumor–derived xenografts with wild-type PIK3CA and KRAS, BRAF, and PTEN mutations were sensitive in vivo.

The lesson is that there are a number of oncogenes in which certain mutations might be sensitive, such as PIK3CA, but some cancers with a variety of mutations may be resistant. “Clearly, the [PIK3CA] pathway is more complicated, and if you are going to study it, we have to be able to tease out the ones that might actually benefit,” he said.

Comprehensive molecular profiling by the Cancer Genome Atlas Research Network (Nature. 2014;511:543-550) indicates that the magnitude of genomic rearrangement in lung cancer is large. Profiling of 230 resected lung adenocarcinomas revealed significant mutation of 18 genes, including RIT1-activating mutations, and 31 cases that were previously classified as wild type were found to be oncogene positive.

About 140 genes can promote tumorigenesis when altered by intragenic mutations (Science. 2013;339:1546-1558). A typical tumor contains 2 to 8 of these driver mutations, which can be classified into 12 core pathways. “Folks have tried to come up with different algorithms, one being that if you have the same codon mutated in at least 2 different tumors, then by definition it might be an oncogene,” Adjei said. Activated genes that promote growth are probably 10% of the driver genes.

“One of the problems we have is that the most common aberrations are actually the tumor suppressor genes [ie, p53 and PTEN]…the problem is that with our current technology, we can’t target those because those genes are deleted…and we don’t have ways of putting them back,” he said.

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