Table 3 Significance of the alterations relevant to sunitinib

RET_H.AMP

RET Amplifications are rare:

• Detected in sporadic anaplastic thyroid cancers and radiation-associated thyroid cancers (Nakashima Hum Path 2007) maybe as a result of genomic instability [17].

• RET amplifications are rare, mainly RET-PTC1 and RET-PTC3 fustions in thyroid cancer (Marina Melillo J Clin Invest 2005) [18].

Therapy Significance:

• Lung tumors harboring RET amplification and PTEN deletion were sensitive to sunitinib therapy (Jones Genome Biol 2010) [19].

• Medullary thyroid cancer patient responds to sunitinib without RET alterations (Bugalho Oncologist 2009) [20].

• Sunitinib inhibits RET/PTC3 fusion phosphorylation causing morphologic reversion of cell transformation (Kim J Clin Endocrinol Metab 2006) [21].

High level of evidence and Significance

• Sunitinib selectively inhibits growth of RET/PTC cells (Jeong Cancer Biol Ther 2011) [22].

• Treatment of papillary thyroid cancer patient, but not follicular thyroid carcinoma, with sunitinib resulted in a dramatic reduction in RET phosphorylation and prolong patient survival (Dawson Anticancer Drugs 2008) [23].

EGFR_H.AMP

Therapy Significance:

• Sunitinib treatment of glioblastoma multiforme xenograft tumors harboring EGFR amplification and PTEN deletion did not impart any in vivo anti-tumor benefit (Joshi PLoS One 2012) [24].

Lowest level of significance

• Sunitinib had minor anti-proliferative effects (IC50 3 μM) in NSCLC cell lines harbor EGFR T790M and KRAS mutations, which are resistant to EGFR inhibitors (Pan J Cancer Res Oncol 2011) [25].

KRAS_H.AMP

Amplification of proto-oncogenes (wild-type version of oncogene) does not necessarily suggest the ability of this alteration to transform cell.

• However, studies do show that over expression of WT ras proteins leads to morphological transformation of cells (Pulciani Mol Cell Biol 1985) [26].

• Focal amplification of KRAS is one of the most common amplification events in lung adenocarcinoma (Weir Nature 2007; Shiraishi Cancer Res 1989) [27],[28].

• Amplification of KRAS is associated with increased protein levels and is quite common in NSCLC (20%; Wagner AJCP 2009) [29].

Therapy Significance: Mixed data on effecitiveness of Sunitinib in KRAS activated tumors.

• Constitutively active KRAS mutants (G12R) were unresponsive to sunitinib cell growth inhibition in thyroid carcinoma cell lines (Piscazzi J Clin Endocrinol Metab 2012) [30].

Low level of evidence and significance

• Sunitinib had minor anti-proliferative effects (IC50 3 μM) in NSCLC cell lines harbor EGFR T790M and KRAS mutations, which are resistant to EGFR inhibitors (Pan J Cancer Res Oncol 2011) [25].

• Sunitinib reduced tumor size and tumor progression, and prolong median survival in KRAS mutant mouse NSCLC model (Gandhi Cancer Prev Res 2009) [31].

PTEN_DEL

Deletion of PTEN in tumors with oncogene amplifications may be a biomarker for increased tumor sensitivity (mixed results below, not conclusive).

• Lung tumors harboring RET amplification and PTEN deletion were sensitive to sunitinib therapy (Jones Genome Biol 2010) [19].

• Sunitinib treatment of glioblastoma multiforme xenograft tumors harboring EGFR amplification and PTEN deletion did not impart any in vivo anti-tumor benefit (Joshi PLoS One 2012) [24].

Low level of evidence and significance

• PDGF-driven mouse glioblastoma tumors in PTEN deficient mice had a moderate effect on survival (D’Amico Neurol Res 2012) [32].

AKT_A117T

• Mutation has not been previously reported

• Sunitinib apoptosis mediated through inhibition of AKT signaling in pediatric medulloblastomas (Yang Mol Cancer Res 2010) [33]. This was likely due to inhibition of upstream RTKs (and no AKT directly).

• Sunitinib decreases phosphorylation of AKT in KIT mutant GIST cell line, as a result of KIT inhibition (Ikezoe Cancer Sci 2006) [34].

Low level of evidence and significance

• Reduction of Phospo-AKT in AML cancers harboring FLT3 mutations (Fiedler Blood 2005) [35].