Table 3.

Significance of the alterations relevant to sunitinib

Gene alteration	Interpretation
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].

Sunitinib relevant genes for basis of sensitivity, specifically RET amplification, PTEN loss, EGFR and KRAS amplification and a detailed literature search from National Library of Medicine’s MEDLINE data base.